Azepane derivatives and methods of treating hepatitis B infections

ABSTRACT

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject. In an embodiment of the compounds provided herein, the compounds are of Formula Va:

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/928,130, filed Jan. 16, 2014, and U.S. application Ser. No.14/511,964, filed Oct. 10, 2014. The entire contents of theseapplications are incorporated herein by reference in their entirety.

BACKGROUND

Chronic hepatitis B virus (HBV) infection is a significant global healthproblem, affecting over 5% of the world population (over 350 millionpeople worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon and nucleoside analogues/inhibitors of the viralpolymerase); drug resistance, low efficacy, and tolerability issueslimit their impact. The low cure rates of HBV are attributed at least inpart to the presence and persistence of covalently closed circular DNA(cccDNA) in the nucleus of infected hepatocytes. However, persistentsuppression of HBV DNA slows liver disease progression and helps toprevent hepatocellular carcinoma. Current therapy goals for HBV-infectedpatients are directed to reducing serum HBV DNA to low or undetectablelevels, and to ultimately reducing or preventing the development ofcirrhosis and hepatocellular carcinoma.

There is a need in the art for therapeutic agents that treat, ameliorateor prevent HBV infection. Administration of these therapeutic agents toan HBV infected patient, either as monotherapy or in combination withother HBV treatments or ancillary treatments, will lead to significantlyimproved prognosis, diminished progression of the disease, and enhancedseroconversion rates.

SUMMARY OF THE INVENTION

Provided herein are compounds useful for the treatment of HBV infectionin a subject in need thereof.

In one aspect, provided herein are compounds having the Formula I:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of Formula I has the Formula II,

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I has the Formula III,

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein are compounds having the Formula IV:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein are compounds having the Formula V:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.

In one aspect, provided herein is a method of treating an HBV infectionin an individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of FormulaI, Ia, Ib, II, III, IV, V, Vx, or Va.

In another aspect, provided herein is a method of eradicating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula I, Ia, Ib, II, III, IV, V, Vx, or Va.

In another aspect, provided herein is a method of reducing viral loadassociated with an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va.

In still another aspect, provided herein is a method of reducingreoccurrence of an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va.

In yet another aspect, provided herein is a method of reducing anadverse physiological impact of an HBV infection in an individual inneed thereof, comprising administering to the individual atherapeutically effective amount of a compound of Formula I, Ia, Ib, II,III, IV, V, Vx, or Va.

Also provided herein are methods of inducing remission of hepatic injuryfrom an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va.

In another aspect, provided herein is a method of reducing thephysiological impact of long-term antiviral therapy for HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of FormulaI, Ia, Ib, II, III, IV, V, Vx, or Va.

In another aspect, provided herein is method of prophylacticallytreating an HBV infection in an individual in need thereof, wherein theindividual is afflicted with a latent HBV infection, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va.

Any of the above methods may further comprise administration to theindividual at least one additional therapeutic agent. In an embodiment,the additional therapeutic agent may be selected from, but not limitedto, the group consisting of a HBV polymerase inhibitor, immunomodulatoryagents, pegylated interferon, viral entry inhibitor, viral maturationinhibitor, capsid assembly modulator, reverse transcriptase inhibitor, acyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and agents ofdistinct or unknown mechanism, and a combination thereof.

In another embodiment, the additional therapeutic agent is selected fromthe group consisting of a HBV polymerase inhibitor, interferon, viralentry inhibitor, viral maturation inhibitor, capsid assembly modulator,reverse transcriptase inhibitor, a TLR-agonist, and agents of distinctor unknown mechanism, and a combination thereof.

In another embodiment, the additional therapeutic agent is a reversetranscriptase inhibitor and is at least one of Zidovudine, Didanosine,Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the additionaltherapeutic agent is a TLR agonist. In a preferred embodiment, the TLRagonist is a TLR-7 agonist selected from the group consisting ofSM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In a further embodiment of the combination therapy, the additionaltherapeutic agent is an interferon, wherein the interferon is anyinterferon, which may be optionally pegylated. In yet a furtherembodiment, the interferon is interferon alpha (IFN-α), interferon beta(IFN-β), interferon lambda (IFN-λ), or interferon gamma (IFN-γ). In apreferred embodiment, the interferon is interferon-alpha-2a,interferon-alpha-2b, interferon-alpha-n1, pegylated interferon-alpha-2a,or pegylated interferon-alpha-2b.

In any of the methods provided herein, the method may further compriseadministering to the individual at least one HBV vaccine, a nucleosideHBV inhibitor, or any combination thereof. In an embodiment, the HBVvaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B,GENEVAC-B, or SHANVAC B.

In another embodiment of the methods provided herein, administering thecompound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va allows foradministering of the at least one additional therapeutic agent at alower dose or frequency as compared to the administering of the at leastone additional therapeutic agent alone that is required to achievesimilar results in prophylactically treating an HBV infection in anindividual in need thereof.

In another embodiment of the methods provided herein, administering thecompound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va reduces theviral load in the individual to a greater extent or at a faster ratecompared to the administering of a compound selected from the groupconsisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, and anycombination thereof.

In another embodiment of the methods provided herein, the administeringof the compound of Formula I, Ia, Ib, II, III, IV, V, Vx, or Va causes alower incidence of viral mutation and/or viral resistance than theadministering of a compound selected from the group consisting of a HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

In another aspect, provided herein is method of treating an HBVinfection in an individual in need thereof, comprising reducing the HBVviral load by administering to the individual a therapeuticallyeffective amount of a compound of Formula I, Ia, Ib, II, III, IV, V, Vx,or Va alone or in combination with a reverse transcriptase inhibitor;and further administering to the individual a therapeutically effectiveamount of HBV vaccine. In an embodiment, the reverse transcriptaseinhibitor is at least one of Zidovudine, Didanosine, Zalcitabine, ddA,Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine,Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir,ganciclovir, valganciclovir, Tenofovir, Adefovir, cidofovir, Efavirenz,Nevirapine, Delavirdine, or Etravirine

In another embodiment of the methods provided herein, the method furthercomprises monitoring the HBV viral load, and wherein the method iscarried out for a period of time such that the HBV virus isundetectable.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds that are useful in the treatment andprevention of HBV infection in man. In a non-limiting aspect, thesecompounds may modulate or disrupt HBV assembly and other HBV coreprotein functions necessary for the generation of infectious particlesby interacting with HBV capsid to afford defective viral particles withgreatly reduced virulence. The compounds of the invention have potentantiviral activity, exhibit favorable metabolic, tissue distribution,safety and pharmaceutical profiles, and are suitable for use in man.

The HBV capsid protein plays essential functions during the viral lifecycle. HBV capsid/core proteins form metastable viral particles orprotein shells that protect the viral genome during intercellularpassage, and also play a central role in viral replication processes,including genome encapsidation, genome replication, and virionmorphogenesis and egress. Capsid structures also respond toenvironmental cues to allow un-coating after viral entry. Consistently,proper capsid assembly and function of core protein have been found tobe critical for viral infectivity.

The crucial function of HBV capsid proteins imposes stringentevolutionary constraints on the viral capsid protein sequence, leadingto the observed low sequence variability and high conservation.Consistently, mutations in HBV capsid that disrupt its assembly arelethal, and mutations that perturb capsid stability severely attenuateviral replication. The more conserved a drug target is, the fewerreplication-competent resistance mutations are acquired by patients.Indeed, natural mutations in HBV capsid for chronically infectedpatients accumulate in only four out of 183 residues in the full lengthprotein. Thus, HBV capsid assembly and function inhibitors may elicitlower drug resistance emergence rates relative to existing HBVantivirals. Further, drug therapy that targets HBV capsid could be lessprone to drug-resistant mutations when compared to drugs that targettraditional neuraminidase enzyme active sites. Reports describingcompounds that bind viral capsids and inhibit replication of HIV,rhinovirus and HBV provide strong pharmacological proof of concept forviral capsid proteins as antiviral drug targets.

In one aspect, the compounds of the invention are useful in HBVtreatment by disrupting, accelerating, reducing, delaying and/orinhibiting normal viral capsid assembly and/or disassembly of immatureor mature particles, thereby inducing aberrant capsid morphology andleading to antiviral effects such as disruption of virion assemblyand/or disassembly, virion maturation, and/or virus egress. In oneembodiment, a disruptor of capsid assembly interacts with mature orimmature viral capsid to perturb the stability of the capsid, thusaffecting assembly and/or disassembly. In another embodiment, adisruptor of capsid assembly perturbs protein folding and/or saltbridges required for stability, function and/or normal morphology of theviral capsid, thereby disrupting and/or accelerating capsid assemblyand/or disassembly. In yet another embodiment, the compounds of theinvention bind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds of theinvention cause failure of the formation of capsid of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds of the invention disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds of the invention disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds of theinvention disrupt and/or accelerate capsid assembly and/or disassemblyduring vial infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, eradication of the HBV from a hostadvantageously obviates the need for chronic long-term therapy and/orreduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit or disrupt) the activity,stability, function, and viral replication properties of HBV cccDNA. Inyet another embodiment, the compounds of the invention can be used inmethods of diminishing or preventing the formation of HBV cccDNA.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit or disrupt) the activity of HBVcccDNA. In yet another embodiment, the compounds of the invention can beused in methods of diminishing or preventing the formation of HBVcccDNA.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±20% or ±10%, more preferably ±5%,even more preferably ±1%, and still more preferably ±0.1% from thespecified value, as such variations are appropriate to perform thedisclosed methods.

As used herein, the term “capsid assembly modulator” refers to acompound that disrupts or accelerates or inhibits or hinders or delaysor reduces or modifies normal capsid assembly (e.g., during maturation)or normal capsid disassembly (e.g., during infectivity) or perturbscapsid stability, thereby inducing aberrant capsid morphology andfunction. In one embodiment, a capsid assembly modulator acceleratescapsid assembly or disassembly, thereby inducing aberrant capsidmorphology. In another embodiment, a capsid assembly modulator interacts(e.g. binds at an active site, binds at an allosteric site, modifiesand/or hinders folding and the like) with the major capsid assemblyprotein (CA), thereby disrupting capsid assembly or disassembly. In yetanother embodiment, a capsid assembly modulator causes a perturbation instructure or function of CA (e.g., ability of CA to assemble,disassemble, bind to a substrate, fold into a suitable conformation, orthe like), which attenuates viral infectivity and/or is lethal to thevirus.

As used herein, the term “treatment” or “treating,” is defined as theapplication or administration of a therapeutic agent, i.e., a compoundof the invention (alone or in combination with another pharmaceuticalagent), to a patient, or application or administration of a therapeuticagent to an isolated tissue or cell line from a patient (e.g., fordiagnosis or ex vivo applications), who has HBV infection, a symptom ofHBV infection or the potential to develop HBV infection, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect HBV infection, the symptoms of HBV infection or thepotential to develop HBV infection. Such treatments may be specificallytailored or modified, based on knowledge obtained from the field ofpharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers toa human or a non-human mammal. Non-human mammals include, for example,livestock and pets, such as ovine, bovine, porcine, canine, feline andmurine mammals. Preferably, the patient, subject or individual is human.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction and/or alleviation ofthe signs, symptoms, or causes of a disease, or any other desiredalteration of a biological system. An appropriate therapeutic amount inany individual case may be determined by one of ordinary skill in theart using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salts” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.

Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the patient. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations. As used herein, “pharmaceuticallyacceptable carrier” also includes any and all coatings, antibacterialand antifungal agents, and absorption delaying agents, and the like thatare compatible with the activity of the compound useful within theinvention, and are physiologically acceptable to the patient.Supplementary active compounds may also be incorporated into thecompositions. The “pharmaceutically acceptable carrier” may furtherinclude a pharmaceutically acceptable salt of the compound useful withinthe invention. Other additional ingredients that may be included in thepharmaceutical compositions used in the practice of the invention areknown in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁₋₆means one to six carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. Most preferred is (C₁₋₆)alkyl, particularly ethyl,methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “cycloalkyl” refers to a mono cyclic orpolycyclic non-aromatic radical, wherein each of the atoms forming thering (i.e., skeletal atoms) is a carbon atom. In one embodiment, thecycloalkyl group is saturated or partially unsaturated. In anotherembodiment, the cycloalkyl group is fused with an aromatic ring.Cycloalkyl groups include groups having 3 to 10 ring atoms (C₃₋₁₀cycloalkyl), or groups having 3 to 7 ring atoms (C₃₋₇ cycloalkyl).Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

Monocyclic cycloalkyls include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Dicyclic cycloalkyls include, but are not limited to,tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycycliccycloalkyls include adamantine and norbornane. The term cycloalkylincludes “unsaturated nonaromatic carbocyclyl” or “nonaromaticunsaturated carbocyclyl” groups, both of which refer to a nonaromaticcarbocycle as defined herein, which contains at least one carbon carbondouble bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers toa heteroalicyclic group containing one to four ring heteroatoms eachselected from O, S and N. In one embodiment, each heterocycloalkyl grouphas from 4 to 10 atoms in its ring system, with the proviso that thering of said group does not contain two adjacent O or S atoms. Inanother embodiment, the heterocycloalkyl group is fused with an aromaticring. In one embodiment, the nitrogen and sulfur heteroatoms may beoptionally oxidized, and the nitrogen atom may be optionallyquaternized. The heterocyclic system may be attached, unless otherwisestated, at any heteroatom or carbon atom that affords a stablestructure. A heterocycle may be aromatic or non-aromatic in nature. Inone embodiment, the heterocycle is a heteroaryl.

An example of a 3-membered heterocycloalkyl group includes, and is notlimited to, aziridine. Examples of 4-membered heterocycloalkyl groupsinclude, and are not limited to, azetidine and a beta lactam. Examplesof 5-membered heterocycloalkyl groups include, and are not limited to,pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-memberedheterocycloalkyl groups include, and are not limited to, piperidine,morpholine and piperazine. Other non-limiting examples ofheterocycloalkyl groups are:

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings),wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples of arylgroups include phenyl, anthracyl, and naphthyl. Preferred examples arephenyl and naphthyl, most preferred is phenyl. In some embodiments, arylgroups have six carbon atoms. In some embodiments, aryl groups have fromsix to ten carbon atoms. In some embodiments, aryl groups have from sixto sixteen carbon atoms.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. In some embodiments, heteroarylor heteroaromatic groups have two to five carbon atoms. In someembodiments, heteroaryl or heteroaromatic groups have from tow to tencarbon atoms. In some embodiments, heteroaryl or heteroaromatic groupshave from two to sixteen carbon atoms. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. In someembodiments, polycyclic heteroaryl groups have two to five carbon atoms.In some embodiments, polycyclic heteroaryl groups have from tow to tencarbon atoms. In some embodiments, polycyclic heteroaryl groups havefrom two to sixteen carbon atoms. Examples include the followingmoieties:

Examples of heteroaryl groups also include pyridyl, pyrazinyl,pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl,furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl,oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles and heteroaryls include indolyl(particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl),1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl),2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl(particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup. The term “substituted” further refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.In one embodiment, the substituents vary in number between one and four.In another embodiment, the substituents vary in number between one andthree. In yet another embodiment, the substituents vary in numberbetween one and two.

As used herein, the term “ddA” refers to 2′,3′-dideoxyadenosine.

COMPOUNDS OF THE INVENTION

The present invention relates to the discovery of compounds that areuseful in the treatment and prevention of HBV infection in man. In oneaspect, the compounds of the invention are useful in HBV treatment bydisrupting, accelerating, reducing delaying or inhibiting normal viralcapsid assembly or disassembly of immature or mature particles, therebyinducing aberrant capsid morphology and leading to antiviral effectssuch as disruption of virion assembly or disassembly or virionmaturation, or virus egress.

In another aspect, compounds of the invention bind to core proteinthereby inducing aberrant virion and leading to antiviral effects suchas disruption of virion assembly, disassembly, maturation, or virusegress.

The capsid assembly disruptors disclosed herein may be used asmonotherapy or in cross-class combination regimens for treating HBVinfection in man. Combination therapy with drugs exhibiting differentmechanism of action (MOA) that act at different steps in the virus lifecycle may deliver greater efficacy due to additive or synergisticantiviral effects. Clinically evaluated HIV treatment regimens haveshown that combination therapy improves the efficacy of viral loadreduction, and dramatically reduces emergence of antiviral resistance.Combination therapy for the treatment of Hepatitis C (HCV) virusinfection has also resulted in significant improvement in sustainedantiviral response and eradication rates. Thus, use of the HBV capsidassembly inhibitors of the present invention in combination with, forexample, neuraminidase drugs, is likely to deliver a more profoundantiviral effect and greater disease eradication rates than currentstandards of care.

Capsid assembly plays a central role in HBV genome replication. HBVpolymerase binds pre-genomic HBV RNA (pgRNA), and pgRNA encapsidationmust occur prior to HBV DNA synthesis. Moreover, it is well establishedthat nuclear accumulation of the cccDNA replication intermediate, whichis responsible for maintenance of chronic HBV replication in thepresence of nucleoside suppressive therapy, requires the capsid forshuttling HBV DNA to the nuclei. Therefore, the HBV capsid assemblydisruptors of the invention have the potential to increase HBVeradication rates through synergistic or additive suppression of viralgenome replication and to further reduce accumulation of cccDNA whenused alone or in combination with existing nucleoside drugs. The capsidassembly disruptors of the present invention may also alter normal coreprotein function or degradation, potentially leading to altered MHC-1antigen presentation, which may in turn increaseseroconversion/eradication rates through immuno-stimulatory activity,more effectively clearing infected cells.

In one aspect, drug resistance poses a major threat to current therapiesfor chronic HBV infection, and cross-class combination therapy is aproven strategy for delaying emergence of drug resistance strains. Thecapsid assembly disruptors of the present invention can, whenadministered alone or in combination with other HBV therapy, offerenhanced drug resistant profiles and improved management of chronic HBV.

The compounds useful within the invention can be synthesized usingtechniques well-known in the art of organic synthesis. The startingmaterials and intermediates required for the synthesis may be obtainedfrom commercial sources or synthesized according to methods known tothose skilled in the art.

In one aspect, the compound of the invention is a compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groupsare optionally substituted 1-5 times with halo, —OH, —CN, or —NO₂;

each R² is, independently at each occurrence, OH, halo, —CN, —NO₂, R⁶,or OR⁶, wherein R⁶ is, independently at each occurrence, —C₁-C₆ alkyl,—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl),wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups are optionally substituted 1-5 times with halo, —OH,—CN, or —NO₂;

Cy is

R⁷ and R⁸ are, independently at each occurrence, —C₁-C₆ alkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), whereinthe aryl or heteroaryl groups are optionally substituted with C₁-C₃alkyl;

or R⁷ and R⁸ join to form a 3- to 10-membered ring;

R¹¹ is, independently at each occurrence, OH, halo, —CN, —NO₂, —C₁-C₆alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl, —C₃-C₁₀cycloalkyl, —C₃-C₁₀ heterocyclo alkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groupsare optionally substituted 1-5 times with halo, —OH, —CN, or —NO₂;

R¹² is, independently at each occurrence, H or —C₁-C₆ alkyl;

R¹³ and R¹⁴ join to form a CH₂ bridge;

m is 0, 1, 2, 3, or 4;

n is 1, 2, 3, or 4;

x is 0, 1, 2, 3, 4, or 5; and

y is 0, 1, 2, 3, or 4.

In another aspect, the compound of the invention is a compound ofFormula Ia:

or a pharmaceutically acceptable salt thereof;

wherein

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groupsare optionally substituted 1-5 times with halo, —OH, —CN, or —NO₂;

each R² is, independently at each occurrence, OH, halo, —CN, —NO₂, R⁶,or OR⁶, wherein R⁶ is, independently at each occurrence, —C₁-C₆ alkyl,—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl),wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups are optionally substituted 1-5 times with halo, —OH,—CN, or —NO₂;

or two R² groups, and the phenyl ring to which they are attached, jointo form benzimidazole;

Cy is

R⁷ and R⁸ are, independently at each occurrence, —C₁-C₆ alkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), whereinthe aryl or heteroaryl groups are optionally substituted with C₁-C₃alkyl;

or R⁷ and R⁸ join to form a 3- to 10-membered ring;

R¹¹ is, independently at each occurrence, OH, halo, —CN, —NO₂, ═O,—OC(O)CH₃, —C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆heteroalkyl, —C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl groups are optionally substituted1-5 times with halo, —OH, —CN, or —NO₂;

R¹² is, independently at each occurrence, H or —C₁-C₆ alkyl;

R¹³ and R¹⁴, together with the carbons to which they are attached, jointo form a cyclopropyl ring;

m is 0, 1, 2, 3, or 4;

n is 1, 2, 3, or 4;

x is 0, 1, 2, 3, 4, or 5; and

y is 0, 1, 2, 3, or 4.

In still another aspect, the compound of the invention is a compound ofFormula Ib:

or a pharmaceutically acceptable salt thereof;

wherein

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),—C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), wherein the alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groupsare optionally substituted 1-5 times with halo, —OH, —CN, or —NO₂;

each R² is, independently at each occurrence, OH, halo, —CN, —NO₂, R⁶,or OR⁶, wherein R⁶ is, independently at each occurrence, —C₁-C₆ alkyl,—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), —C₁-C₄ alkyl-(C₃-C₁₀heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl),wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups are optionally substituted 1-5 times with halo, —OH,—CN, or —NO₂;

or two R² groups, and the phenyl ring to which they are attached, jointo form benzimidazole;

Cy is

R⁷ and R⁸ are, independently at each occurrence, —C₁-C₆ alkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl), whereinthe aryl or heteroaryl groups are optionally substituted with C₁-C₃alkyl;

or R⁷ and R⁸ join to form a 3- to 10-membered ring;

R¹¹ is, independently at each occurrence, OH, halo, —CN, —NO₂, ═O,—OC(O)CH₃, —H₂PO₄, —C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl,—O—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —O—C₃-C₁₀ cycloalkyl, —C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl),—C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄alkyl-(heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl groups are optionally substituted1-5 times with halo, —OH, —CN, or —NO₂;

R¹² is, independently at each occurrence, H or —C₁-C₆ alkyl;

R¹³ and R¹⁴, together with the carbons to which they are attached, jointo form a cyclopropyl ring;

m is 0, 1, 2, 3, or 4;

n is 1, 2, 3, or 4;

x is 0, 1, 2, 3, 4, or 5; and

y is 0, 1, 2, 3, or 4.

In one embodiment of Formula Ib provided herein, x is 0, 1, 2, or 3.

In another embodiment of Formula Ib provided herein, x is 1, 2, or 3.

In one embodiment of Formula I provided herein,

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, —C₁-C₄ alkyl-(C₃-C₁₀cycloalkyl), or —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), wherein thealkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups areoptionally substituted 1-3 times with halo, —OH, —CN, or —NO₂;

each R² is, independently at each occurrence, OH, halo, —CN, —NO₂, R⁶,or OR⁶, wherein R⁶ is, independently at each occurrence, —C₁-C₆ alkyl,—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, —C₁-C₄alkyl-(C₃-C₁₀ cycloalkyl), or —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl),wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groupsare optionally substituted 1-3 times with halo, —OH, —CN, or —NO₂;

Cy is

R⁷ and R⁸ are, independently at each occurrence, —C₁-C₆ alkyl, aryl,heteroaryl, —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl);

or R⁷ and R⁸ join to form a 3- to 7-membered ring;

R¹¹ is, independently at each occurrence, OH, halo, —CN, —NO₂, —C₁-C₆alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ hetero alkyl, —O—C₁-C₆ hetero alkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), or —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), wherein the alkyl,heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionallysubstituted 1-3 times with halo, —OH, —CN, or —NO₂;

R¹² is, independently at each occurrence, H or —C₁-C₆ alkyl;

m is 0, 1, 2, or 3;

n is 1, 2, or 3;

x is 0, 1, 2, or 3; and

y is 0, 1, 2, or 3.

In another embodiment of Formula I provided herein,

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, or —O—C₁-C₆ heteroalkyl, wherein thealkyl group is optionally substituted 1-3 times with halo or —OH;

each R² is, independently at each occurrence, OH, halo, R⁶, or OR⁶,wherein R⁶ is, independently at each occurrence, —C₁-C₆ alkyl, —C₃-C₁₀cycloalkyl, —C₁-C₄ alkyl-(C₃-C₁₀ cycloalkyl), wherein the alkyl andcycloalkyl groups are optionally substituted 1-3 times with halo or —OH;

Cy is

R¹¹ is, independently at each occurrence, OH, halo, —C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, or —O—C₁-C₆ heteroalkyl, wherein thealkyl group is optionally substituted 1-3 times with halo or —OH;

R¹² is, independently at each occurrence, H or —C₁-C₆ alkyl;

m is 0, 1, 2, or 3;

n is 1, 2, or 3;

x is 0, 1, 2, or 3; and

y is 0, 1, 2, or 3.

In one embodiment of Formula I provided herein, R⁴ is H.

In another embodiment of Formula I provided herein, R⁷ and R⁸ are,independently at each occurrence, —C₁-C₆ alkyl, phenyl, pyridyl, benzyl,or pyridylmethyl.

In another embodiment of Formula I provided herein, R⁷ and R⁸ are,independently at each occurrence, —C₁-C₆ alkyl, wherein the —C₁-C₆ alkylgroups join to form a 3- to 7-membered ring.

In another embodiment of Formula I provided herein, each R¹ is,independently at each occurrence, halo, and x is 1, 2, or 3.

In a further embodiment of Formula I provided herein, the compound is ofthe Formula II:

or a pharmaceutically acceptable salt thereof, wherein X¹ is halo.

In another embodiment of Formula I and Formula II provided herein, eachR² is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH.

In one specific embodiment, each R² is, independently at eachoccurrence, halo or —C₁-C₃ alkyl-OH, and y is 1 or 2.

In still another embodiment of Formula I and Formula II provided herein,each R² is, independently at each occurrence, OR⁶, wherein R⁶ is,independently at each occurrence, —C₁-C₆ alkyl or —C₃-C₁₀ cyclo alkyl,wherein the alkyl and cycloalkyl groups are optionally substituted 1-2times with halo or OH.

In a further embodiment of Formula I and Formula II provided herein, thecompound is of Formula III:

or a pharmaceutically acceptable salt thereof.

In still another embodiment of Formulas I-III provided herein, Cy is

In one specific embodiment, each R¹¹ is, independently at eachoccurrence, halo, OH, —C₁-C₆ alkyl, or —O—C₁-C₆ alkyl, wherein the alkylgroup is optionally substituted 1-3 times with halo or OH.

In yet another embodiment of Formulas I-III provided herein, Cy is

and n is 0, 1, or 2. In one specific embodiment, R¹¹ is —O—C₁-C₃ alkyl,and n is 1. In another specific embodiment, R¹¹ is OH or —C₁-C₃alkyl-OH, and n is 1. In another specific embodiment, n is 0. In anotherspecific embodiment, R¹¹ is halo, and n is 1. In still another specificembodiment, R¹¹ is —C₁-C₃ alkyl, and n is 1.

In a further embodiment of Formulas I-III provided herein, Cy is

wherein X² is halo and n is 0, 1, or 2. In one specific embodiment, n is0.

In another embodiment of Formulas I-III provided herein, Cy is

In one specific embodiment, each R¹¹ is, independently at eachoccurrence, OH or —C₁-C₃ alkyl, wherein the alkyl group is optionallysubstituted 1-3 times with halo or OH, and m is 1 or 2. In anotherspecific embodiment, m is 0.

In another aspect, provided herein is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof;

wherein

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ hetero alkyl, —O—C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl,—C₁-C₄ alkyl-(C₃-C₁₀ cyclo alkyl), —C₁-C₄ alkyl-(C₃-C₁₀heterocycloalkyl), —C₁-C₄ alkyl-(aryl), or —C₁-C₄ alkyl-(heteroaryl),wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl groups are optionally substituted 1-5 times with halo, —OH,—CN, or —NO₂;

each R³ is, independently at each occurrence, OH, —CN, —NO₂, —C₁-C₆alkyl, —C₁-C₆ alkoxy, R⁹, or OR⁹, wherein R⁹ is, independently at eachoccurrence, —C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀heterocycloalkyl, aryl, heteroaryl, —(CH₂)₁₋₄—(C₃-C₁₀ cyclo alkyl),—(CH₂)₁₋₄—(C₃-C₁₀ heterocycloalkyl), —(CH₂)₁₋₄-(aryl), or—(CH₂)₁₋₄-(heteroaryl), wherein the alkyl group is substituted 1-5 timeswith halo, —OH, —CN, or —NO₂; and the alkoxy, —(CH₂)₁₋₄—, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionallysubstituted 1-5 times with halo, —OH, —CN, or —NO₂;

x is 0, 1, 2, 3, 4, or 5; and

z is 1, 2, 3, or 4.

In one embodiment of Formula IV provided herein,

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —CN, —NO₂,—C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —O—C₁-C₆ heteroalkyl,—C₃-C₁₀ cycloalkyl, —C₃-C₁₀ heterocycloalkyl, —C₁-C₄ alkyl-(C₃-C₁₀cycloalkyl), or —C₁-C₄ alkyl-(C₃-C₁₀ heterocycloalkyl), wherein thealkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups areoptionally substituted 1-3 times with halo, —OH, —CN, or —NO₂;

each R³ is, independently at each occurrence, OH, —CN, —NO₂, —C₁-C₆alkyl, —C₁-C₆ alkoxy, R⁹, or OR⁹, wherein R⁹ is, independently at eachoccurrence, —C₁-C₆ heteroalkyl, —C₃-C₁₀ cycloalkyl, —C₃-C₁₀heterocycloalkyl, —(CH₂)₁₋₄—(C₃-C₁₀ cycloalkyl), or —(CH₂)₁₋₄—(C₃-C₁₀heterocycloalkyl), wherein the alkyl group is substituted 1-3 times withhalo, —OH, —CN, or —NO₂; and the alkoxy, —(CH₂)₁₋₄—, heteroalkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted 1-3 timeswith halo, —OH, —CN, or —NO₂;

x is 0, 1, 2, or 3; and

z is 1, 2, or 3.

In another embodiment of Formula IV provided herein,

R⁴ is H or C₁-C₃ alkyl;

each R¹ is, independently at each occurrence, OH, halo, —C₁-C₆ alkyl,—O—C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, or —O—C₁-C₆ heteroalkyl, wherein thealkyl group is optionally substituted 1-3 times with halo or —OH;

each R³ is, independently at each occurrence, OH, —C₁-C₆ alkyl, —C₁-C₆alkoxy, R⁹, or OR⁹, wherein R⁹ is, independently at each occurrence,—C₃-C₁₀ cycloalkyl or —(CH₂)₁₋₄—(C₃-C₁₀ cycloalkyl), wherein the alkylgroup is substituted 1-3 times with halo or —OH; and the alkoxy,—(CH₂)₁₋₄—, and cycloalkyl groups are optionally substituted 1-3 timeswith halo or —OH;

x is 0, 1, 2, or 3; and

z is 1, 2, or 3.

In another embodiment of Formula IV provided herein, R⁴ is H.

In another embodiment of Formula IV provided herein, each R¹ is,independently at each occurrence, halo and x is 1, 2, or 3.

In still another embodiment of Formula IV provided herein, each R³ is,independently at each occurrence, OH or —C₁-C₆ alkyl, wherein the alkylgroup is substituted 1-3 times with halo or —OH and z is 1, 2, or 3.

In yet another embodiment of Formula IV provided herein, R³ is —C₁-C₃alkyl-OH and z is 1.

In another embodiment of Formula I provided herein, the compound is ofFormula V:

or a pharmaceutically acceptable salt thereof;

wherein

each R¹ is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

each R² is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

Cy is

R¹¹ is, independently at each occurrence, —OH, halo, —C₁-C₆ alkyl,—OC(O)CH₃, or —C₃-C₁₀ cycloalkyl;

R¹³ and R¹⁴, together with the carbons to which they are attached, jointo form a cyclopropyl ring;

m is 1, 2, or 3;

n is 1, 2, or 3; and

x is 2 or 3.

In another embodiment of Formula I provided herein, the compound is ofFormula Vx:

or a pharmaceutically acceptable salt thereof;

wherein

each R¹ is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

each R² is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

Cy is

R¹¹ is, independently at each occurrence, —OH, halo, —C₁-C₆ alkyl,—OC(O)CH₃, or —C₃-C₁₀ cycloalkyl;

R¹³ and R¹⁴, together with the carbons to which they are attached, jointo form a cyclopropyl ring;

m is 1, 2, or 3;

n is 1, 2, or 3; and

x is 1, 2, or 3.

In a specific embodiment of Formula V provided herein, each R¹ is,independently at each occurrence, halo.

In another specific embodiment of Formula V provided herein, each R² is,independently at each occurrence, halo or —C₁-C₆ alkyl, wherein thealkyl is optionally substituted 1-3 times with halo.

In yet another embodiment of Formula I provided herein, the compound isof Formula Va:

or a pharmaceutically acceptable salt thereof;

wherein

each R¹ is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

each R² is, independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or—O—C₁-C₆ alkyl, wherein the alkyl group is optionally substituted 1-3times with halo or OH;

Cy is

R¹¹ is, independently at each occurrence, —OH, halo, —C₁-C₆ alkyl,—OC(O)CH₃, —H₂PO₄, or —C₃-C₁₀ cycloalkyl;

R¹³ and R¹⁴, together with the carbons to which they are attached, jointo form a cyclopropyl ring;

m is 1, 2, or 3;

n is 1, 2, or 3; and

x is 1, 2, or 3.

In one specific embodiment of Formula Va provided herein, x is 2 or 3.

In another specific embodiment of Formula Va provided herein, each R¹is, independently at each occurrence, halo.

In still another specific embodiment of Formula Va provided herein, eachR² is, independently at each occurrence, halo or —C₁-C₆ alkyl, whereinthe alkyl is optionally substituted 1-3 times with halo.

In yet another specific embodiment of Formula Va provided herein, Cy is

and R¹¹ is, independently at each occurrence, —OH, halo, —C₁-C₆ alkyl,—OC(O)CH₃, or —H₂PO₄, wherein n and m are 1, 2, or 3, and at least oneR¹¹ is H₂PO₄.

Certain preferred embodiments of Formulas I, Ia, Ib, II, III, IV, V, Vx,and Va, including pharmaceutically acceptable salts thereof, are shownbelow in Table 1 and in Table 2. All compounds of Formulas I, Ia, Ib,II, III, IV, V, Vx, and Va as well as pharmaceutically acceptable saltsthereof, and the compounds of Table 1 and Table 2, as well aspharmaceutically acceptable salts thereof, are considered to be“compounds of the invention.”

Synthetic method codes refer to the synthesis methodologies provided inthe experimental section. For example, “A01B01C01D01” refers the use ofintermediate A01 for region A, intermediate B01 for region B,intermediate C01 for region C, and intermediate D01 for region D.

TABLE 1 Compound MS Synthetic Structure ID ¹H NMR (M + H)⁺ method

1762 ¹H NMR (400 MHz, MeOD) δ 8.46 (dd, J = 2.4, 6.7 Hz, 1H), 8.26-8.22(m, 1H), 7.66-7.56 (m, 2H), 7.51 (dd, J = 8.7, 10.0 Hz, 1H), 3.96- 3.86(m, 1H), 3.77 (dd, J = 4.3, 14.2 Hz, 1H), 3.64-3.54 (m, 1H), 3.25- 3.14(m, 1H), 3.02 (dd, J = 8.4, 14.3 Hz, 1H), 2.01-1.97 (m, J = 4.3, 8.3,12.7 Hz, 1H), 1.92-1.50 (m, 5H). 447 GENERAL PROCEDURE A A01B02C02

1763 445/447 GENERAL PROCEDURE A A01B02C01

1763_E1 ¹H NMR (400 MHz, DMSO-d6) δ = 10.69 (s, 1H), 8.40-8.45 (m, 1H),8.25-8.35 (m, 1H), 8.00-8.05 (m, 1H), 7.70-7.80 (m, 2H), 7.40- 7.50 (m,1H), 4.90-4.92 (m, 1H), 3.60-3.80 (m, 2H), 3.45- 3.55 (m, 1H), 3.05-3.15(m, 1H), 2.85-2.95 (m, 1H), 1.35-1.85 (m, 6H). 445/447 Separated from1763 through Supercritical Fluid Chromato- graphy

1763_E2 ¹H NMR (400 MHz, DMSO-d6) δ = 10.69 (s, 1H), 8.40-8.45 (m, 1H),8.25-8.35 (m, 1H), 8.00-8.05 (m, 1H), 7.70-7.80 (m, 2H), 7.40- 7.50 (m,1H), 4.90-4.92 (m, 1H), 3.60-3.80 (m, 2H), 3.45- 3.55 (m, 1H), 3.05-3.15(m, 1H), 2.85-2.95 (m, 1H), 1.35-1.85 (m, 6H). 445/447 Separated from1763 through Supercritical Fluid Chromato- graphy

1764 429 GENERAL PROCEDURE A A01B02C03

1765 447 GENERAL PROCEDURE A A02B02C02

1766 ¹H NMR (400 MHz, MeOD) δ 8.49- 8.41 (m, 1H), 8.28-8.20 (m, 1H),7.99 (dd, J = 2.5, 6.7 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.50 (dd, J =8.7, 9.9 Hz, 1H), 7.31-7.21 (m, 1H), 3.92-3.83 (m, 1H), 3.54-3.44 (m,2H), 3.42-3.35 (m, 2H), 2.08- 1.88 (m, 3H), 1.81-1.66 (m, 3H) 445/447GENERAL PROCEDURE A A02B02C01

1766_E1 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.44-8.46 (m, 1H), 8.20- 8.25(m, 1H), 7.96-7.99 (m, 1H), 7.60-7.65 (m, 1H), 7.47-7.52 (m, 1H),7.24-7.29 (m, 1H), 3.85- 3.92 (m, 1H), 3.45-3.55 (m, 2H), 3.35-3.41 (m,2H), 1.90- 2.05 (m, 3H), 1.65-1.80 (m, 3H). 445/447 Separated from 1763through Supercritical Fluid Chromato- graphy

1766_E2 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.44-8.46 (m, 1H), 8.20- 8.25(m, 1H), 7.96-7.99 (m, 1H), 7.60-7.65 (m, 1H), 7.47-7.52 (m, 1H),7.24-7.29 (m, 1H), 3.85- 3.92 (m, 1H), 3.45-3.55 (m, 2H), 3.35-3.41 (m,2H), 1.90- 2.05 (m, 3H), 1.65-1.80 (m, 3H). 445/447 Separated from 1766through Supercritical Fluid Chromato- graphy

1767 ¹HNMR (400 MHz, MeOD) δ 8.45 (dd, J = 2.4, 6.7 Hz, 1H), 8.26-8.22(m, 1H), 7.87-7.81 (m, 1H), 7.55- 7.40 (m, 2H), 7.32-7.24 (m, 1H),3.93-3.81 (m, 1H), 3.54-3.44 (m, 2H), 3.42-3.34 (m, 2H), 2.10- 1.87 (m,3H), 1.83-1.61 (m, 3H) 429 GENERAL PROCEDURE A A01B02C03

1768 ¹H NMR (400 MHz, MeOD) δ 8.34 (d, J = 1.76 Hz, 1H), 8.16-8.22 (m,1H), 7.95-8.05 (m, 2H), 7.60-7.66 (m, 1H), 7.21-7.29 (m, 1H), 5.02 (d, J= 6.27 Hz, 2H), 4.73-4.80 (m, 1H), 3.66-3.79 (m, 1H), 3.51-3.63 (m, 1H),3.41-3.51 (m, 1H), 3.33- 3.39 (m, 1H), 1.91-2.10 (m, 2H), 1.72-1.89 (m,3H), 1.50-1.67 (m, 1H) 459/461 GENERAL PROCEDURE B A03B03C01

1769 ¹H NMR (400 MHz, MeOD) δ 8.40- 8.49 (m, 1H), 8.18-8.29 (m, 1H),7.93-8.01 (m, 1H), 7.58-7.67 (m, 1H), 7.49 (dd, J = 8.72, 9.98 Hz, 1H),7.26 (t, J = 8.97 Hz, 1H), 3.34- 3.55 (m, 2H), 3.15-3.28 (m, 2H),1.67-1.89 (m, 5H), 1.48-1.62 (m, 1H), 1.28 (s, 3H) 459/461 GENERALPROCEDURE B A04B03C01

1784 ¹H NMR (400 MHz, MeOD) δ 8.47 (d, J = 1.9 Hz, 1H), 8.19 (dd, J =8.1, 1.8 Hz, 1H), 7.94-8.04 (m, 2H), 7.67-7.63 (m, 1H), 7.27 (t, J = 8.9Hz, 1H), 5.10 (s, 2H), 4.27-4.18 (m, 1H), 2.94 (t, J = 7.3 Hz, 2H),2.18-2.01 (m, 1H), 1.95-1.80 (m, 2H), 1.70 (dd, J = 12.7, 7.3 Hz, 1H),1.56-1.42 (m, 3H), 1.28-1.23 (m, 1H), 1.13-0.99 (m, 1H) 453/455 GENERALPROCEDURE B A14B03C01

1791 437 GENERAL PROCEDURE B A14B03C03

1820 ¹H NMR (400 MHz, MeOD) δ 8.45- 8.47 (m, 1H), 8.24 -8.26 (m, 1H),7.48-7.63 (m, 3H), 3.78- 3.91 (m, 1H), 3.75-3.76 (m, 1H), 3.51-3.60 (m,1H), 3.18-3.33 (m, 1H), 2.99-3.05 (m, 1H), 1.58- 2.03 (m, 5H). 465GENERAL PROCEDURE A A07B02C02

1821 447 GENERAL PROCEDURE A A07B02C03

1821_D1 ¹H NMR (400 MHz, DMSO-d6) δ = 10.73 (s, 1H), 8.36-8.46 (m, 1H),8.25-8.35 (m, 1H), 7.87-7.95 (m, 1H), 7.65-7.76 (m, 1H), 7.45- 7.55 (m,2H), 5.54-5.56 (m, 2H), 4.25-4.41 (m, 1H), 3.50-3.70 (m, 2H), 3.40-3.45(m, 1H), 2.98- 3.10 (m, 2H), 1.55-2.10 (m, 4H). 447 Separated from 1821through Supercritical Fluid Chromato- graphy

1821_D2 ¹H NMR (400 MHz, DMSO-d6) δ = 10.72 (s, 1H), 8.39-8.45 (m, 1H),8.30-8.37 (m, 1H), 7.87-7.95 (m, 1H), 7.60-7.70 (m, 1H), 7.45- 7.55 (m,2H), 5.39-5.41 (m, 1H), 4.60-4.70 (m, 1H), 3.85-3.95 (m, 1H), 3.45-3.55(m, 2H), 3.07- 3.20 (m, 2H), 2.05-2.15 (m, 1H), 1.61-1.85 (m, 3H).. 447Separated from 1821 through Supercritical Fluid Chromato- graphy

1822 463/465 GENERAL PROCEDURE A A07B02C01

1822_D1 ¹H NMR (400 MHz, DMSO-d6) δ = 10.70 (s, 1H), 8.38-8.41 (m, 1H),8.26-8.37 (m, 1H), 8.03-8.06 (m, 1H), 7.70-7.73 (m, 2H), 7.43- 7.48 (m,1H), 5.54-5.56 (m, 1H), 4.25-4.40 (m, 1H), 3.35-3.65 (m, 3H), 3.01-3.08(m, 2H), 1.64- 1.90 (m, 4H). 463/465 Separated from 1822 throughSupercritical Fluid Chromato- graphy

1822_D2 ¹H NMR (400 MHz, DMSO-d6) δ = 10.70 (s, 1H), 8.38-8.41 (m, 1H),8.26-8.37 (m, 1H), 8.03-8.06 (m, 1H), 7.67-7.72 (m, 2H), 7.43- 7.48 (m,1H), 5.38-5.40 (m, 1H), 4.68-4.83 (m, 1H), 3.85-3.92 (m, 1H), 3.50-3.57(m, 2H), 3.09- 3.19 (m, 2H), 2.07-2.10 (m, 1H), 1.65-1.85 (m, 3H).463/465 Separated from 1822 through Supercritical Fluid Chromato- graphy

1829 465 GENERAL PROCEDURE A A08B02C02

1829_D1 ¹H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.38-8.45 (m, 1H),8.25-8.35 (m, 1H), 7.69-7.74 (m, 3H), 5.09-5.29 (m, 1H), 4.25- 4.78 (m,1H), 3.44-3.90 (m, 3H), 3.05-3.20 (m, 1H), 1.50- 1.90 (m, 4H). 465Separated from 1822 through Supercritical Fluid Chromato- graphy

1829_D2 ¹H NMR (400 MHz, DMSO-d6) δ = 10.82 (s, 1H), 8.40-8.43 (m, 1H),8.25-8.35 (m, 1H), 7.69-7.74 (m, 3H), 5.09-5.25 (m, 1H), 4.40- 4.78 (m,1H), 3.48-3.90 (m, 3H), 3.05-3.17 (m, 1H), 1.50- 1.90 (m, 4H). 465Separated from 1822 through Supercritical Fluid Chromato- graphy

1830 447 GENERAL PROCEDURE A A08B02C03

1831 ¹H NMR (400 MHz, MeOD) δ 8.46- 8.48 (m, 1H), 8.23-8.28 (m, 1H),7.97-7.99 (m, 1H), 7.62- 7.63 (m, 1H), 7.49-7.54 (m, 1H), 7.24-7.29 (m,1H), 4.33-4.46 (m, 1H), 3.60-3.75 (m, 3H), 3.35- 3.45 (m, 1H), 3.17-3.21(m, 1H), 1.85-1.95 (m, 2H), 1.68- 1.76 (m, 2H). 463/465 GENERALPROCEDURE A A08B02C01

1832 465 GENERAL PROCEDURE A A09B02C02

1833 ¹H NMR (400 MHz, MeOD) δ 8.43- 8.46 (m, 1H), 8.23-8.25 (m, 1H),7.80-7.86 (m, 1H), 7.44- 7.53 (m, 2H), 7.26-7.31 (m, 1H), 4.41-4.53 (m,1H), 3.77-3.81 (m, 1H), 3.41-3.72 (m, 4H), 1.73- 2.25 (m, 4H). 447GENERAL PROCEDURE A A08B02C03

1834 463/465 GENERAL PROCEDURE A A08B02C01

1890 ¹H NMR (400 MHz, MeOD) δ 8.17- 8.34 (m, 1H), 7.61-7.74 (m, 2H),7.27 (s, 4H), 4.08 (s., 2H), 3.22- 3.29 (m, 1H), 2.55-2.81 (m, 2H),1.77-2.26 (m, 5H), 0.57-0.77 (m, 4H) 459/461 GENERAL PROCEDURE AA05B02C01

1891 ¹H NMR (400 MHz, MeOD) δ 8.42-8.47 (m, 1H), 8.20-8.26 (m, 1H),7.79-7.87 (m, 1H), 7.40-7.53 (m, 2H), 7.22-7.32 (m, 1H), 3.36- 3.53 (m,2H), 3.17-3.28 (m, 2H), 1.70-1.83 (m, 5H), 1.51-1.61 (m, 1H), 1.28 (s,3H) 443 GENERAL PROCEDURE A A05B02C03

1892 ¹H NMR (400 MHz, MeOD) δ 8.43-8.47 (m, 1H), 8.19-8.27 (m, 1H),7.56-7.64 (m, 2H), 7.46-7.53 (m, 1H), 3.37-3.52 (m, 3H), 3.19- 3.27 (m,1H), 1.70-1.82 (m, 5H), 1.46-1.64 (m, 1H), 1.28 (s, 3H) 461 GENERALPROCEDURE A A05B02C02

1893 ¹H NMR (400 MHz, MeOD) δ = 8.51-8.27 (m, 2 H), 8.03-7.98 (m, 1 H),7.71-7.52 (m, 2 H), 7.27 (t, J = 8.8 Hz, 1H), 4.11-3.62 (m, 7 H),3.43-3.17 (m, 2 H). 447/449 GENERAL PROCEDURE A A13B02C01

1893_E1 447/449 Separated from 1893 through Supercritical FluidChromato- graphy

1893_E2 447/449 Separated from 1893 through Supercritical FluidChromato- graphy

1894 431 GENERAL PROCEDURE A A13B02C03

1895 449 GENERAL PROCEDURE A A13B02C02

1896 ¹H NMR (400 MHz, MeOD) δ 8.51- 8.26 (m, 2 H), 8.06-7.98 (m, 1 H),7.71-7.52 (m, 2 H), 7.27 (t, J = 8.8 Hz, 1H), 4.26-4.17 (m, 1 H), 3.81-3.03 (m, 8 H), 2.83 (s, 3H). 460/462 GENERAL PROCEDURE A A10B02C01

1897 444 GENERAL PROCEDURE A A10B02C03

1898 ¹H NMR (400 MHz, MeOD) δ 8.49- 8.21 (m, 2 H), 7.68-7.52 (m, 3 H),4.27-4.18 (m, 1 H), 3.79-3.02 (m, 8 H), 2.78 (s, 3H). 462 GENERALPROCEDURE A A10B02C02

1899 444/446 GENERAL PROCEDURE A A11B02C01

1900 ¹H NMR (400 MHz, CD₃OD) δ 8.47- 8.49 (m, 1 H), 8.25-8.27 (m, 1 H),7.78-7.85 (m, 1H), 7.46-7.54 (m, 2 H), 7.28-7.32 (m, 1H), 4.14 (s, 2 H),3.67 (t, J = 6.0 Hz, 2 H), 3.35-3.37 (m, 2 H), 1.90-2.03 (m, 2 H). 428GENERAL PROCEDURE A A11B02C03

1901 446 GENERAL PROCEDURE A A11B02C02

1902 ¹H NMR (400 MHz, CD₃OD) δ 8.46- 8.48 (m, 1 H), 8.23-8.27 (m, 1 H),8.00-8.02 (m, 1 H), 7.64-7.67 (m, 1H), 7.52 (t, J = 8.4 Hz, 1 H), 7.28(t, J = 8.8 Hz, 1 H), 4.20 (s, 2 H), 3.65 (t, J = 5.6 Hz, 2 H), 3.57 (t,J = 5.2 Hz, 2 H), 2.89 (s, 3 H), 1.92- 1.96 (m, 2 H). 458/460 GENERALPROCEDURE A A12B02C01

1903 442 GENERAL PROCEDURE A A12B02C03

1904 460 GENERAL PROCEDURE A A12B02C02

1907 1H NMR (400 MHz, MeOD) δ 8.40- 8.51 (m, 1H), 8.22-8.31 (m, 1H),7.95-8.02 (m, 1H), 7.59-7.69 (m, 1H), 7.46-7.56 (m, 1H), 7.21-7.34 (m,1H), 3.65-3.75 (m, 1H), 3.46 (s, 3H), 3.36-3.41 (m, 2H), 3.20- 3.31 (m,2H), 3.10-3.19 (m, 1H), 1.85-2.21 (m, 2H), 1.43-1.83 ppm (m, 2H) 474/476GENERAL PROCEDURE A A16B02C01

1908 1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 8.29-8.19 (m, 1H), 8.03-7.93 (m, 1H), 7.68-7.57 (m, 1H), 7.54-7.46 (m, 1H), 7.30-7.23 (m, 1H),3.71-3.56 (m, 2H), 3.49- 3.42 (m, 1H), 3.41 (s, 3H), 3.29- 3.16 (m, 2H),3.16-3.08 (m, 1H), 2.05-1.88 (m, 2H), 1.74-1.56 (m, 2H) 474/476 GENERALPROCEDURE A A17B02C01

1909 1H NMR (400 MHz, MeOD) δ 8.49- 8.41 (m, 1H), 8.29-8.20 (m, 1H),8.03-7.94 (m, 1H), 7.67-7.59 (m, 1H), 7.55-7.46 (m, 1H), 7.31- 7.22 (m,1H), 4.01-3.94 (m, 1H), 3.89-3.82 (m, 1H), 3.71-3.59 (m, 2H), 3.26-3.09(m, 2H), 2.08- 1.92 (m, 2H), 1.81-1.63 (m, 2H) 460/462 GENERAL PROCEDUREA A18B02C01

1910 ¹H NMR (400 MHz, MeOD) δ 8.38 (d, J = 1.9 Hz, 1H), 8.08-8.04 (m,1H), 8.00-7.96 (m, 1H), 7.67- 7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.27 (s,1H), 3.96-3.86 (m, 1H), 3.56-3.35 (m, 4H), 2.68 (s, 3H), 2.10-1.89 (m,3H), 1.85-1.65 (m, 3H) 441/443 GENERAL PROCEDURE A A02B04C01

1911 ¹H NMR (400 MHz, MeOD) δ 8.39- 8.36 (m, 1H), 8.09-8.04 (m, 1H),8.01-7.96 (m, 1H), 7.67-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.30- 7.24 (m,1H), 3.95-3.84 (m, 1H), 3.55-3.35 (m, 4H), 2.68 (s, 3H), 2.10-1.91 (m,3H), 1.85-1.65 (m, 3H) 425 GENERAL PROCEDURE A A02B04C03

1912 443 GENERAL PROCEDURE A A02B04C02

1913 441 GENERAL PROCEDURE A A01B04C01

1914 425 GENERAL PROCEDURE A A01B04C03

1915 443 GENERAL PROCEDURE A A01B04C02

1917 443 GENERAL PROCEDURE F A02B05C03

1918 461 GENERAL PROCEDURE F A02B05C02

1921 461 GENERAL PROCEDURE F A01B05C02

1928 427/429 GENERAL PROCEDURE A A02B01C01

1929 ¹H NMR (400 MHz, MeOD) δ 8.38 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H),7.95-8.08 (m, 2 H), 7.77 (t, J = 7.8 Hz, 1 H), 7.61-7.69 (m, 1 H),7.28(t, J = 9.0 Hz, 1 H), 3.85-3.94 (m, 1 H), 3.69 (dd, J = 4.5, 14.0 Hz, 1H), 3.54 (td, J = 6.5, 13.2 Hz, 1 H), 3.09-3.20 (m, 1 H), 2.96 (dd, J =8.3, 14.0 Hz, 1 H), 1.43-2.03 (m, 6 H). 427/429 GENERAL PROCEDURE AA01B01C01

1932 459/561 GENERAL PROCEDURE A A06B02C01

1938 ¹H NMR (400 MHz, MeOD) δ 8.44 (dd, J = 2.3, 6.6 Hz, 1H), 8.25- 8.23(m, 1H), 7.85-7.84 (m, 1H), 7.55-7.41 (m, 2H), 7.35-7.23 (m, 1H),3.62-3.49 (m, 2H), 3.32- 3.26 (m, 2H), 2.11-1.94 (m, 1H), 1.85-1.62 (m,5H), 1.26 (s, 3H) 443 GENERAL PROCEDURE A A06B02C03

1944 461 GENERAL PROCEDURE A A06B02C02

1934_D1 459/461 GENERAL PROCEDURE A A30B02C01

1934_D2 NMR 459/461 GENERAL PROCEDURE A A30B02C01

1940_D1 NMR 443 GENERAL PROCEDURE A A30B02C03

1940_D2 443 GENERAL PROCEDURE A A30B02C03

1946_D1 461 GENERAL PROCEDURE A A30B02C02

1946_D2 461 GENERAL PROCEDURE A A30B02C02

2041 459/461 GENERAL PROCEDURE A A30B02C01

2042 443 GENERAL PROCEDURE A A31B02C03

2043 461 GENERAL PROCEDURE A A31B02C02

_1935_D1 459/461 GENERAL PROCEDURE A A32B02C01

_1935_D2 459/461 GENERAL PROCEDURE A A32B02C01

_1941_D1 ¹H NMR (400 MHz, MeOD) δ 8.48 (dd, J = 6.65, 2.13 Hz, 1 H),8.26 (d, J = 2.51 Hz, 1 H), 7.81 (ddd, J = 12.49, 7.34, 2.26 Hz, 1 H),7.53 (t, J = 9.29 Hz, 1 H), 7.45 (d, J = 9.03 Hz, 1 H), 7.26-7.36 (m, 1H), 4.06- 4.17 (m, 1 H), 3.83 (d, J = 15.81 Hz, 1 H), 3.56-3.66 (m, 1H), 3.08- 3.18 (m, l H), 1.84-2.07 (m, 3 H), 1.29-1.62 (m, 3 H), 0.91(d, J = 6.27 Hz, 3 H). 443 GENERAL PROCEDURE A A32B02C03

_1941_D2 ¹H NMR (400 MHz, MeOD) δ 8.49 (dd, J = 6.78, 2.26 Hz, 1 H),8.20- 8.29 (m, l H), 7.84 (ddd, J = 12.74, 7.34, 2.51 Hz, 1 H),7.41-7.57 (m, 2 H), 7.25-7.34 (m, 1 H), 3.98- 4.14 (m, 2 H), 3.74 (d, J= 15.31 Hz, 1 H), 3.38 (d, J = 4.77 Hz, 1 H), 1.87-1.99 (m, 2 H),1.61-1.84 (m, 4 H), 0.92 (d, J = 6.27 Hz, 3 H). 443 GENERAL PROCEDURE AA32B02C03

_1947_D1 461 GENERAL PROCEDURE A A32B02C02

_1947_D2 461 GENERAL PROCEDURE A A32B02C02

_2065_D1 459/461 GENERAL PROCEDURE A A33B02C01

_2065_D2 459/461 GENERAL PROCEDURE A A33B02C01

_2066_D1 443 GENERAL PROCEDURE A A33B02C03

_2066_D2 443 GENERAL PROCEDURE A A33B02C03

_2067_D1 461 GENERAL PROCEDURE A A33B02C02

_2067_D2 461 GENERAL PROCEDURE A A33B02C02

1950_D1 475/477 GENERAL PROCEDURE A A21B02C01

1950_D2 475/477 GENERAL PROCEDURE A A21B02C01

1951_D1 459 GENERAL PROCEDURE A A21B02C03

1951_D2 459 GENERAL PROCEDURE A A21B02C03

1952_D1 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.45-8.48 (m, 1H), 8.24- 8.26(m, 1H), 7.59-7.64 (m, 2H), 7.49-7.55 (m, 1H), 3.80- 3.85 (m, 1H),3.60-3.65 (m, 1 H), 3.30-3.55 (m, 7H), 2.26-2.29 (m, 1H), 2.05-2.10 (m,1H), 1.70- 1.84 (m, 2H). 477 GENERAL PROCEDURE A A21B02C02

1952_D2 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.45-8.48 (m, 1H), 8.23- 8.26(m, 1H), 7.59-7.64 (m, 2H), 7.48-7.54 (m, 1H), 4.02- 4.07 (m, 1H),3.66-3.72 (m, 2H), 3.55-3.60 (m, 1H), 3.32-3.39 (m, 5H), 1.96-2.18 (m,3H), 1.75- 1.79 (m, 1H). 477 GENERAL PROCEDURE A A21B02C02

1956_D1 475/477 GENERAL PROCEDURE A A21B02C01

1956_D2 475/477 GENERAL PROCEDURE A A21B02C01

1957_D1 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.47-8.49 (m, 1H), 8.25- 8.27(m, 1H), 7.80-7.85 (m, 1H), 7.44-7.54 (m, 2H), 7.27- 7.31 (m, 1H),3.93-3.95 (m, 1H), 3.45-3.64 (m, 4H), 3.34 (s, 3H), 3.06-3.09 (m, 1H),2.04 -2.07 (m, 2H), 1.52-1.61 (m, 2H). 459 GENERAL PROCEDURE A A21B02C03

1957_D2 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.46-8.48 (m, 1H), 8.24- 8.27(m, 1H), 7.80-7.85 (m, 1H), 7.44-7.55 (m, 2H), 7.27- 7.33 (m, 1H),3.86-3.92 (m, 3H), 3.60-3.65 (m, 1H), 3.34 (s, 3H), 2.99-3.03 (m, 1H),2.88-2.91 (m, 1H), 1.98-2.01 (m, 1H), 1.77- 1.84 (m, 3H). 459 GENERALPROCEDURE A A20B02C03

1958_D1 477 GENERAL PROCEDURE A A20B02C02

1958_D2 477 GENERAL PROCEDURE A A20B02C02

1959 ¹H NMR (400 MHz, MeOD) δ 8.45 (dd, J = 2.3, 6.7 Hz, 1 H), 8.25(ddd, J = 2.4, 4.6, 8.6 Hz, 1 H), 7.98 (dd, J = 2.6, 6.8 Hz, 1 H), 7.64(ddd, J = 2.6, 4.2, 9.0 Hz, 1 H), 7.50 (dd, J = 8.7, 9.9 Hz, 1 H), 7.27(t, J = 9.0 Hz, 1 H), 3.77-3.68 (m, 1 H), 3.64- 3.49 (m, 2 H), 3.44-3.37(m, 5 H), 3.27-3.20 (m, 1 H), 2.10 (tdd, J = 2.9, 7.6, 15.2 Hz, 1 H),2.05-1.97 (m, 1H), 1.84-1.70 (m, 2 H) 475/477 GENERAL PROCEDURE AA15B02C01

1960 459 GENERAL PROCEDURE A A15B02C03

1961 477 GENERAL PROCEDURE A A15B02C02

1971 458 GENERAL PROCEDURE A A16B02C03

1972 458 GENERAL PROCEDURE A A17B02C03

1973 476 GENERAL PROCEDURE A A16B02C02

1974 476 GENERAL PROCEDURE A A17B02C02

1975 431 GENERAL PROCEDURE A A13B01C02

1976 413 GENERAL PROCEDURE A A13B01C03

1977 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.40 (t, J = 1.6 Hz, 1H), 8.23(d, J = 8.2 Hz, 1H), 8.10-8.05 (m, 1H), 8.00 (dd, 7=2.6,6.8 Hz, 1H),7.78 (t, J = 7.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.28 (t,J = 9.0 Hz, 1H),4.06-3.98 (m, 1H), 3.93-3.84 (m, 2H), 3.80-3.59 (m, 4H), 3.27 (ddd, J =3.6, 8.2, 13.8 Hz, 1H), 3.15 (dd, J = 7.3, 14.1 Hz, 1H) 429/431 GENERALPROCEDURE A A13B01C01

1978 461 GENERAL PROCEDURE A A13B06C02

1979 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.50 (d, J = 2.3 Hz, 1H), 8.22(dd, J = 2.4, 8.8 Hz, 1H), 7.83 (ddd, J = 2.5, 7.4, 12.8 Hz, 1H),7.47-7.42 (m, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.32-7.23 (m, 1H), 4.07 (s,3H), 4.06-3.99 (m, 1H), 3.96-3.88 (m, 2H), 3.88-3.79 (m, 2H), 3.74- 3.64(m, 2H), 3.30-3.24 (m, 1H), 3.13 (dd, J = 7.5, 14.6 Hz, 1H) 443 GENERALPROCEDURE A A13B06C03

1980 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.50 (d, J = 2.3 Hz, 1H), 8.22(dd, J = 2.4, 8.7 Hz, 1H), 7.97 (dd, J = 2.6, 6.7 Hz, 1H), 7.65-7.59 (m,1H), 7.37 (d, J = 8.7 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H), 4.07 (s, 3H),4.05- 3.98 (m, 1H), 3.96-3.88 (m, 2H), 3.87-3.78 (m, 2H), 3.73-3.64 (m,2H), 3.31-3.24 (m, 1H), 3.13 (dd, J = 7.6, 14.5 Hz, 1H) 459/461 GENERALPROCEDURE A A13B06C01

1981 463 GENERAL PROCEDURE F A13B05C02

1982 ¹H NMR (400 MHz, METHANOL- d₄) δ 8.41-8.50 (m, 1H), 8.20-8.28 (m,1H), 7.80-7.95 (m, 2H), 7.40- 7.51 (m, 1H), 7.19-7.34 (m, 1H), 5.90-5.99(m, 1H), 5.76-5.85 (m, 1H), 3.99-4.06 (m, 1H), 3.84-3.95 (m, 2H),3.59-3.83 (m, 4H), 3.38- 3.47 (m, 1H), 3.33-3.36 (m, 1H) 445 GENERALPROCEDURE F A13B05C03

1984 463 GENERAL PROCEDURE A A35B02C02

1985 445 GENERAL PROCEDURE A A35B02C03

1986 461/463 GENERAL PROCEDURE A A35B02C01

1987 489 GENERAL PROCEDURE A A36B02C02

1988 471 GENERAL PROCEDURE A A36B02C03

1989 487/489 GENERAL PROCEDURE A A36B02C01

2002 445 GENERAL PROCEDURE F A53B05C02

2003 427 GENERAL PROCEDURE F A53B05C03

2004 443 GENERAL PROCEDURE F A53B05C01

2005 479 GENERAL PROCEDURE F A07B05C02

2006 461 GENERAL PROCEDURE F A07B05C03

2008 ¹H NMR (400 MHz, METHANOL- d₄) δ 8.34-8.45 (m, 1H), 8.16-8.28 (m,1H), 7.84-7.97 (m, 1H), 7.53- 7.69 (m, 2H), 5.88-5.94 (m, 1H), 5.77-5.82(m, 1H), 4.77-4.82 (m, 1H), 4.64-4.71 (m, 1H), 4.41-4.49 (m, 1H),4.30-4.37 (m, 1H), 3.99- 4.10 (m, 1H), 3.34-3.83 (m, 5H), 3.17-3.28 (m,1H), 1.82-2.08 (m, 2H), 1.65-1.80 (m, 2H) 479 GENERAL PROCEDURE FA08B05C02

2009 461 GENERAL PROCEDURE F A08B05C03

2010 ¹H NMR (400 MHz, METHANOL- d₄) δ 8.36-8.42 (m, 1H), 8.21-8.27 (m,1H), 7.95-8.01 (m, 1H), 7.86- 7.93 (m, 1H), 7.60-7.68 (m, 1H), 7.26 (s,1H), 5.88-5.95 (m, 1H), 5.75-5.82 (m, 1H), 4.77-4.82 (m, 1H), 4.65-4.72(m, 1H), 4.40-4.49 (m, 1H), 4.30-4.38 (m, 1H), 3.97- 4.12 (m, 1H),3.49-3.83 (m, 3H), 3.34-3.43 (m, 1H), 3.19-3.28 (m, 1H), 1.80-2.07 (m,2H), 1.65-1.80 (m, 2H) 477 GENERAL PROCEDURE F A08B05C01

2011 ¹H NMR (400 MHz, METHANOL- d₄) δ 8.34-8.41 (m, 1H), 8.19-8.25 (m,1H), 7.86-7.94 (m, 1H), 7.56- 7.67 (m, 2H), 5.90 (s, 1H), 5.78 (s, 1H),4.71-4.78 (m, 1H), 4.49-4.57 (m, 1H), 4.37-4.46 (m, 1H), 4.04- 4.16 (m,1H), 3.82-3.93 (m, 1H), 3.46 (s, 4H), 1.93-2.29 (m, 3H), 1.73-1.92 (m,1H) 447 GENERAL PROCEDURE F A09B05C02

2012 461 GENERAL PROCEDURE F A08B05C03

1821_Trans ¹HNMR (MeOD-d4, 400 MHz) 8.47 (dd, J = 6.7, 2.3 Hz, 1H),8.24-8.28 (m, 1H), 7.81-7.87 (m, 1H), 7.41- 7.56 (m, 2H), 7.23-7.34 (m,1H), 4.24-4.50 (m, 1H), 3.64-3.91 (m, 2H), 3.45-3.59 (m, 1H), 3.07- 3.26(m, 2H), 1.63-2.16 (m, 4H) 447 GENERAL PROCEDURE A A07_transB0 2C03

1821_Cis 447 GENERAL PROCEDURE A A07_CisB02C 03

2007_Trans 477/479 GENERAL PROCEDURE A A07_transB0 5C01

2007_Cis ¹HNMR (MeOD-d4, 400 MHz) 8.40 (s, 1H), 8.25 (dd, J = 8.1, 1.6Hz, 1H), 7.99 (dd, J = 6.7, 2.6 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.61-7.71 (m, 1H), 7.25-7.30 (m, 1H), 5.75-6.00 (m, 2H), 3.90-4.10 (m, 1H),3.57-3.72 (m, 2H), 3.36 (s, 1H), 3.30 (s, 1H), 3.18-3.27 (m, 1H),2.15-2.31 (m, 1H), 1.69- 2.06 (m, 3H) 477/479 GENERAL PROCEDURE AA07_CisB05C 01

2008_Trans ¹HNMR(MeOD-d4, 400 MHz) 8.41 (s, 1H), 8.25 (dd, J = 8.0, 1.8Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.57- 7.68 (m, 2H), 5.93 (s, 1H),5.81 (s, 1H), 4.29-4.52 (m, 1H), 3.60- 3.85 (m, 3H), 3.36-3.44 (m, 1H),3.24-3.32 (m, 1H), 1.62-2.03 (m, 4H) 479 GENERAL PROCEDURE A A08_transB05C02

2008_Cis ¹HNMR (MeOD-d4, 400 MHz) 8.40 (s, 1H), 8.25 (dd, J = 8.0, 1.8Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.54-7.71 (m, 2H), 5.75-5.98 (m, 2H),4.66-4.85 (m, 1H), 4.00- 4.13 (m, 1H), 3.49-3.79 (m, 3H), 3.22-3.29 (m,1H), 1.86-2.13 (m, 2H), 1.64-1.81 (m, 2H) 479 GENERAL PROCEDURE AA08_CisB05C 02

2010_Trans 477/479 GENERAL PROCEDURE A A08_transB0 5C01

2010_Cis 477/479 GENERAL PROCEDURE A A08_CisB05C 01

2013_Cis ¹HNMR (400 MHz, METHANOL-d₄) δ = 8.36 (s, 1H), 8.23 (d, J = 8.0Hz, 1H), 7.98 (dd, J = 2.5, 6.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),7.68-7.60 (m, 1H), 7.26 (t, J = 8.9 Hz, 1H), 5.90 (s, 1H), 5.78 (s, 1H),4.86- 4.71 (m, 1H), 4.16-4.03 (m, 1H), 3.65-3.52 (m, 2H), 3.34 (d, J =4.3 Hz, 2H), 2.31-2.18 (m, 1H), 2.15- 1.83 (m, 3H) 477/479 GENERALPROCEDURE F A08_cisB05C 01

2013_Trans ¹HNMR (400 MHz, METHANOL-d₄) δ = 8.38 (s, 1H), 8.23 (d, J =8.0 Hz, 1H), 7.98 (dd, J = 2.5, 6.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),7.67-7.60 (m, 1H), 7.26 (t, J = 8.9 Hz, 1H), 5.90 (s, 1H), 5.79 (s, 1H),4.56- 4.38 (m, 1H), 3.92-3.81 (m, 1H), 3.58 (m, 1H), 3.52-3.42 (m, 2H),3.41-3.33 (m, 2H), 2.25-2.10 (m, 1H), 2.09-1.93 (m, 2H), 1.85- 1.74 (m,1H) 477/479 GENERAL PROCEDURE F A08_transB0 5C01

2018 ¹H NMR (400 MHz, DMSO-d6) δ = 10.62 (s, 1H), 8.11 (s, 1H), 8.04-8.07 (m, 2H), 7.82 (s, 1H), 7.72- 7.74 (m, 1H), 7.43-7.48 (m, 1H),4.57-4.58 (m, 1H), 3.60-3.70 (m, 1H), 3.25-3.34 (m, 2H), 3.17- 3.20 (m,2H), 2.52 (s, 3H), 1.49- 1.82 (m, 6H). 441/443 GENERAL PROCEDURE EA02B07C01

2020 443 GENERAL PROCEDURE E A02B07C02

2021 1H NMR (400 MHz, DMSO-d6) δ = 10.73-10.69 (m, 1H), 8.43-8.38 (m,1H), 8.34-8.28 (m, 1H), 8.08- 8.03 (m, 1H), 7.75-7.66 (m, 2H), 7.50-7.42(m, 1H), 5.28-5.22 (m, 1H), 4.95-4.88 (m, 1H), 3.95- 3.84 (m, 1H),3.62-3.51 (m, 2H), 3.17-3.09 (m, 2H), 2.02 (s, 4H), 1.81-1.53 (m, 3H)503/505 GENERAL PROCEDURE A A54B02C01

2022 1H NMR (400 MHz, DMSO-d6) δ = 10.82-10.68 (m, 1H), 8.42-8.35 (m,1H), 8.34-8.28 (m, 1H), 8.08- 8.03 (m, 1H), 7.76-7.65 (m, 2H), 7.50-7.42(m, 1H), 5.11-4.79 (m, 2H), 3.94-3.81 (m, 1H), 3.57- 3.50 (m, 1H),3.47-3.41 (m, 2H), 3.31-3.28 (m, 1H), 2.02 (s, 3H), 1.95-1.54 (m, 4H)503/505 GENERAL PROCEDURE A A55B02C01

2023 1H NMR (400 MHz, DMSO-d6) δ = 10.71-10.68 (m, 1H), 8.41-8.37 (m,1H), 8.34-8.28 (m, 1H), 8.08- 8.03 (m, 1H), 7.74-7.69 (m, 2H), 7.49-7.43(m, 1H), 5.09-5.00 (m, 2H), 3.62-3.57 (m, 2H), 3.42- 3.38 (m, 2H),3.32-3.30 (m, 1H), 3.19-3.16 (m, 1H), 2.03 (s, 3H), 2.01-2.00 (m, 3H),1.91-1.67 (m, 2H) 545/546 GENERAL PROCEDURE A A56B02C01

2024 ¹H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.37-8.39 (m, 1H),8.27-8.30 (m, 1H), 7.69-7.74 (m, 3H), 4.86-4.90 (m, 1H), 3.53- 3.55 (m,1H), 3.30-3.40 (m, 1H), 3.15-3.25 (m, 1H), 2.33 (s, 3H), 1.80-1.90 (m,1H), 1.65- 1.75 (m, 4H), 1.45-1.55 (m, 4H). 489 GENERAL PROCEDURE AA56B02C02

2025 ¹H NMR (400 MHz, DMSO-d6) δ = 10.71 (s, 1H), 8.40-8.45 (m, 1H),8.27-8.35 (m, 1H), 8.00-8.05 (m, 1H), 7.65-7.75 (m, 2H), 7.43- 7.48 (m,1H), 4.87-4.90 (m, 1H), 3.53-3.55 (m, 2H), 3.30- 3.40 (m, 1H), 3.20-3.25(m, 1H), 1.99 (s, 3H), 1.45-1.90 (m, 6H). 487/489 GENERAL PROCEDURE AA56B02C01

2026 487/489 GENERAL PROCEDURE A A57B02C01

2033 1H NMR (400 MHz, METHANOL- d4) δ 8.53-8.61 (m, 1H), 8.39-8.46 (m,1H), 8.25-8.33 (m, 1H),7.95- 8.03 (m, 1H), 7.59-7.71 (m, 1H), 7.20-7.34(m, 1H), 3.73-3.85 (m, 1H), 3.35-3.59 (m, 4H), 1.78-2.05 (m, 3H),1.54-1.77 (m, 3H) 467/469 GENERAL PROCEDURE G A02B08C01

2044 ¹H NMR (400 MHz, DMSO-d6) δ = 10.70 (s, 1H), 8.40-8.43 (m, 1H),8.27-8.35 (m, 1H), 8.04-8.06 (m, 1H), 7.69-7.74 (m, 2H), 7.43- 7.48 (m,1H), 3.58-3.61 (m, 2H), 3.47-3.49 (m, 2H), 2.50- 2.62 (m, 4H), 1.75-1.78(m, 2H). 443/445 GENERAL PROCEDURE A A58B02C01

2081 1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 2.01 Hz, 1 H), 8.23 (dd, J =8.66, 2.13 Hz, 1 H), 7.96 (dd, J = 6.78, 2.51 Hz, 1 H), 7.70 (d, J =8.78 Hz, 1 H), 7.59-7.65 (m, 1 H), 7.27 (t, J = 8.91 Hz, 1 H), 4.07-4.13 (m, 1 H), 4.03 (t, J = 6.53 Hz, 1 H), 3.77-3.97 (m, 4 H), 3.61-3.73 (m, 2 H), 3.21-3.30 (m, 1 H), 3.11 (dd, J = 14.56, 7.53 Hz, 1 H),0.84-1.04 (m, 4 H). 485/487 GENERAL PROCEDURE C A13B09C01

2082 487 GENERAL PROCEDURE C A13B09C02

2083 469 GENERAL PROCEDURE C A13B09C03

2205 1H NMR (400 MHz, MeOD) δ 8.32 (s, 1 H), 8.24 (d, J = 7.2 Hz, 1 H),7.99 (d, J = 6.8 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.64-7.65 (m, 1H), 7.27 (t, J = 7.2 Hz, 1 H), 4.57-4.73 (m, 2 H), 3.95-3.96 (m, 1 H),3.56- 3.62 (m, 2 H), 3.00-3.15 (m, 2 H), 2.85-2.93 (m, 2 H), 1.31-1.85(m, 6 H). 473/475 GENERAL PROCEDURE D A02B12C01

2206 475 GENERAL PROCEDURE D A02B12C02

2207 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.44-8.34 (m, 1H), 8.29- 8.21(m, 1H), 8.10-8.06 (m, 1H), 8.03-7.98 (m, 1H), 7.69-7.63 (m, 1H),7.32-7.24 (m, 1H), 5.71- 5.63 (m, 1H), 5.58-5.50 (m, 1H), 4.07-3.98 (m,1H), 3.92-3.85 (m, 2H), 3.80-3.58 (m, 5H), 3.31- 3.24 (m, 1H), 3.21-3.13(m, 1H) 459/461 GENERAL PROCEDURE F A02B10C01

2208 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.37-8.32 (m, 1H), 8.28- 8.22(m, 1H), 8.08-7.96 (m, 2H), 7.72-7.61 (m, 1H), 7.34-7.22 (m, 1H),5.67-5.62 (m, 1H), 5.56- 5.51 (m, 1H), 3.91-3.78 (m, 1H), 3.47-3.38 (m,2H), 3.31-3.25 (m, 2H), 2.05-1.59 (m, 6H) 461/463 GENERAL PROCEDURE FA13B10C01

2113 455 GENERAL PROCEDURE A A06B06C03

2114_D1 475/477 GENERAL PROCEDURE A A08B06C01

2114_D2 475/477 GENERAL PROCEDURE A A08B06C01

2115_D1 477 GENERAL PROCEDURE A A08B06C02

2115_D2 477 GENERAL PROCEDURE A A08B06C02

2116_D1 459 GENERAL PROCEDURE A A08B06C03

2116_D2 459 GENERAL PROCEDURE A A08B06C03

2117 447/449 GENERAL PROCEDURE A A03B02C01

2118 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.45-8.48 (m, 1H), 8.24- 8.27(m, 1H), 7.59-7.64 (m, 2H), 7.47-7.53 (m, 1H), 4.70- 4.90 (m, 1H),3.70-3.81 (m, 1H), 3.40-3.60 (m, 2H), 3.25-3.35 (m, 1H), 1.75-2.05 (m,5H), 1.55- 1.65 (m, 1H). 449 GENERAL PROCEDURE A A03B02C02

2119 431 GENERAL PROCEDURE A A03B02C03

2120 465/467 GENERAL PROCEDURE A A19B02C01

2121 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.46-8.49 (m, 1H), 8.27- 8.29(m, 1H), 7.53-7.64 (m, 3H), 3.82-3.89 (m, 2H), 3.33- 3.42 (m, 2H),2.13-2.17 (m, 2H), 1.85-1.89 (m, 2H), 1.74-1.78 (m, 2H). 467 GENERALPROCEDURE A A03B02C02

2122 449 GENERAL PROCEDURE A A03B02C03

2123 447/449 GENERAL PROCEDURE A A04B02C01

2124 449 GENERAL PROCEDURE A A04B02C02

2125 431 GENERAL PROCEDURE A A04B02C03

2126 465/467 GENERAL PROCEDURE A A60B02C01

2127 ¹H NMR (400 MHz, METHANOL- d4) δ = 8.50-8.41 (m, 1H), 8.30- 8.21(m, 1H), 7.69-7.42 (m, 3H), 3.56-3.43 (m, 4H), 2.44-2.10 (m, 4H),2.02-1.80 (m, 2H) 467 GENERAL PROCEDURE A A60B02C02

2128 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.52-8.41 (m, 1H), 8.31- 8.20(m, 1H), 7.90-7.76 (m, 1H), 7.59-7.42 (m, 2H), 7.36-7.20 (m, 1H),3.59-3.44 (m, 4H), 2.34- 2.10 (m, 4H), 1.98-1.85 (m, 2H) 449 GENERALPROCEDURE A A60B02C03

2129 449/451 GENERAL PROCEDURE A A60B02C01

2130 451 GENERAL PROCEDURE A A60B02C02

2131 433 GENERAL PROCEDURE A A60B02C03

2132 467 GENERAL PROCEDURE A A61B02C01

2133 ¹H NMR (400 MHz, METHANOL- d₄) δ ppm 3.50-3.61 (m, 2 H) 3.86-4.10(m, 6 H) 7.49-7.68 (m, 3 H) 8.26-8.34 (m, 1 H) 8.46- 8.54 (m, 1 H) 469GENERAL PROCEDURE A A61B02C02

2134 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.53-8.47 (m, 1H),8.34- 8.26 (m,1H), 7.91-7.80 (m, 1H), 7.60-7.52 (m, 1H), 7.49-7.42 (m, 1H), 7.34-7.24(m, 1H), 4.08- 3.89 (m, 6H), 3.59-3.51 (m, 2H) 451 GENERAL PROCEDURE AA61B02C03

2179 ¹H NMR (400 MHz, METHANOL- d₄) δ = 8.52-8.48 (m, 1H), 8.26- 8.18(m, 1H), 8.01-7.93 (m, 1H), 7.65-7.58 (m, 1H), 7.40-7.35 (m, 1H),7.30-7.22 (m, 1H), 5.01- 4.94 (m, 1H), 4.88-4.80 (m, 1H), 4.19-4.07 (m,4H), 4.04-3.88 (m, 3H), 3.71-3.62 (m, 2H), 3.52- 3.40 (m, 1H) 461/463GENERAL PROCEDURE A A60B06C01

2180 463 GENERAL PROCEDURE A A60B06C02

2181 \ 445 GENERAL PROCEDURE A A60B06C03

2182 479/481 GENERAL PROCEDURE A A61B06C01

2492 1H NMR (400 MHz, MeOD) δ 8.48 (dd, J = 6.78, 2.26 Hz, 1 H), 8.24(ddd, J = 8.60, 4.58, 2.38 Hz, 1 H), 7.99 (dd, J = 6.53, 2.51 Hz, 1 H),7.64 (ddd, J = 8.91, 4.14, 2.51 Hz, 1 H), 7.50 (dd, J = 9.79, 8.78 Hz, 1H), 7.27 (t, J = 9.03 Hz, 1 H), 4.28 (dd, J = 15.18, 5.90 Hz, 1 H), 4.07(d, J = 13.30 Hz, 1H), 3.89 (t, J = 9.54 Hz, 1 H), 2.57 (dd, J = 13.18,9.91 Hz, 1 H), 2.37-2.50 (m, 2 H), 1.25-1.36 (m, 2 H), 0.83-1.01 (m, 2H), 0.37 (q, J = 5.02 Hz, 1 H). 457/459 GENERAL PROCEDURE A A25B02C01

2493 1H NMR (400 MHz, MeOD) δ 8.41 (s, 1 H), 8.22 (d, J = 6.78 Hz, 1 H),7.94-8.02 (m, 1 H), 7.83-7.92 (m, 1 H), 7.59-7.68 (m, 1 H), 7.20- 7.30(m, 1 H), 5.85-5.94 (m, 1 H), 5.73-5.82 (m, 1 H), 4.25 (dd, J= 15.06,5.52 Hz, 1 H), 3.81-3.97 (m, 2 H), 2.50-2.70 (m, 2 H), 2.42 (dd, J =14.18, 6.15 Hz, 1 H), 1.29- 1.38 (m, 2 H), 0.84-1.03 (m, 2 H), 0.37 (d,J = 4.52 Hz, 1 H). 471/473 GENERAL PROCEDURE F A25B00C01

2495 475/477 GENERAL PROCEDURE F A35B05C01

2496 ¹H NMR (400 MHz, MeOD) δ 8.49- 8.41 (m, 1H), 8.28-8.20 (m, 1H),7.99 (dd, J = 2.5, 6.7 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.50 (dd, J =8.7, 9.9 Hz, 1H), 7.31-7.21 (m, 1H), 3.92-3.83 (m, 1H), 3.54-3.44 (m,2H), 3.42-3.35 (m, 2H), 2.08- 1.88 (m, 3H), 1.81-1.66 (m, 3H) 477GENERAL PROCEDURE F A25B02C02

2498 ¹HNMR (400 MHz, MeOD) δ 8.45 (dd, J = 2.4, 6.7 Hz, 1H), 8.26-8.22(m, 1H), 7.87-7.81 (m, 1H), 7.55- 7.40 (m, 2H), 7.32-7.24 (m, 1H),3.93-3.81 (m, 1H), 3.54-3.44 (m, 2H), 3.42-3.34 (m, 2H), 2.10- 1.87 (m,3H), 1.83-1.61 (m, 3H) 493/495 GENERAL PROCEDURE F A34B05C01

2499 ¹H NMR (400 MHz, MeOD) δ 8.34 (d, J = 1.76 Hz, 1H), 8.16-8.22 (m,1H), 7.95-8.05 (m, 2H), 7.60-7.66 (m, 1H), 7.21-7.29 (m, 1H), 5.02 (d, J= 6.27 Hz, 2H), 4.73-4.80 (m, 1H), 3.66-3.79 (m, 1H), 3.51-3.63 (m, 1H),3.41-3.51 (m, 1H), 3.33- 3.39 (m, 1H), 1.91-2.10 (m, 2H), 1.72-1.89 (m,3H), 1.50-1.67 (m, 1H) 495/517 GENERAL PROCEDURE F A34B05C02

2500 ¹H NMR (400 MHz, MeOD) δ 8.40- 8.49 (m, 1H), 8.18-8.29 (m, 1H),7.93-8.01 (m, 1H), 7.58-7.67 (m, 1H), 7.49 (dd, J = 8.72, 9.98 Hz, 1H),7.26 (t, J = 8.97 Hz, 1H), 3.34- 3.55 (m, 2H), 3.15-3.28 (m, 2H),1.67-1.89 (m, 5H), 1.48-1.62 (m, 1H), 1.28 (s, 3H) 477 GENERAL PROCEDUREF A34B05C03

2501 519/521 GENERAL PROCEDURE F A62B05C01

2502 ¹HNMR (MeOD-d4, 400 MHz) 8.46 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H),7.92 (d, J = 8.2 Hz, 1H), 7.57-7.71 (m, 2H), 5.77-6.00 (m, 2H), 3.41-3.93 (m, 10H), 3.33-3.36 (m, 3H), 1.83 (t, J = 6.5 Hz, 2H) 521 GENERALPROCEDURE F A62B05C02

2503 503 GENERAL PROCEDURE F A62B05C03

2510 479/451 GENERAL PROCEDURE F A34B02C01

2511 481 GENERAL PROCEDURE F A34B02C02

2512 ¹H NMR (400 MHz, MeOD) δ 8.45- 8.47 (m, 1H), 8.24-8.26 (m, 1H),7.48-7.63 (m, 3H), 3.78- 3.91 (m, 1H), 3.75-3.76 (m, 1H), 3.51-3.60 (m,1H), 3.18-3.33 (m, 1H), 2.99-3.05 (m, 1H), 1.58- 2.03 (m, 5H). 463GENERAL PROCEDURE A A34B02C03

2513 505/507 GENERAL PROCEDURE A A62B02C01

2514 507 GENERAL PROCEDURE A A62B02C02

2515 489 GENERAL PROCEDURE A A62B02C03

2504 ¹HNMR (MeOD-d4, 400 MHz) δ 8.48 (s, 1H), 8.26 (d, J = 8.3 Hz,1H),8.00 (dd, J = 6.7, 2.5 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.64-7.68(m, 1H), 7.28 (t, J = 9.0 Hz, 1H), 5.79-6.03 (m, 2H), 3.44-3.98 (m, 8H),0.94- 1.08 (m, 1H), 0.24-0.51 (m, 4H) 501/503 GENERAL PROCEDURE AA36B05C01

2505 503 GENERAL PROCEDURE A A36B05C02

2506 485 GENERAL PROCEDURE A A36B05C03

2547 441 GENERAL PROCEDURE A A25B02C03

2548 ¹H NMR (400 MHz, MeOD) δ 8.47 (dd, J = 6.53, 2.01 Hz, 1 H), 8.23(ddd, J = 8.47, 4.45, 2.38 Hz, 1 H), 7.61 (dd, J = 9.91, 6.40 Hz, 2 H),7.49 (t, J = 9.29 Hz, 1 H), 4.27 (dd, J = 15.18, 5.90 Hz, 1 H), 4.06 (d,J = 12.05 Hz, 1 H), 3.82-3.93 (m, 1 H), 2.57 (dd, J = 13.05, 10.04 Hz, 1H), 2.35-2.50 (m, 2 H), 1.25-1.36 (m, 2 H), 0.84-1.00 (m, 2 H), 0.36 (q,J = 4.77 Hz, 1 H). 459 GENERAL PROCEDURE A A25B02C02

2549 455 GENERAL PROCEDURE A A25B05C03

2550 473 GENERAL PROCEDURE A A25B05C02

1930 459/461 GENERAL PROCEDURE A A24B02C01

1936 1H NMR (400 MHz, METHANOL- d4) δ 8.37-8.53 (m, 1H), 8.12-8.28 (m,1H), 7.76-7.91 (m, 1H), 7.37- 7.55 (m, 2H), 7.18-7.33 (m, 1H), 4.25 (d,J = 6.65 Hz, 1H), 3.93-4.07 (m, 1H), 3.71 (s, 1H), 3.34-3.52 (m, 1H),2.69-3.17 (m, 1H), 1.47- 2.01 (m, 5H), 1.12 (d, J = 6.90 Hz, 2H),0.88-1.03 (m, 1H) 443 GENERAL PROCEDURE A A24B02C03

1942 461 GENERAL PROCEDURE A A24B02C02

1931_D1 1H NMR (400 MHz, METHANOL- d4) δ 8.39-8.49 (m, 1H), 8.18-8.28(m, 1H), 7.92-8.02 (m, 1H), 7.57- 7.68 (m, 1H), 7.42-7.54 (m, 1H),7.20-7.33 (m, 1H), 3.47-3.55 (m, 1H), 3.37-3.46 (m, 1H), 3.25-3.29 (m,1H), 3.15-3.23 (m, 1H), 2.97- 3.08 (m, 1H), 1.86-2.02 (m, 2H), 1.58-1.83(m, 3H), 1.03 (d, J = 6.90 Hz, 3H) 459/461 GENERAL PROCEDURE A A24B02C01

1931_D2 1H NMR (400 MHz, METHANOL- d4) δ 8.40-8.46 (m, 1H), 8.18-8.26(m, 1H), 7.93-8.00 (m, 1H), 7.58- 7.65 (m, 1H), 7.43-7.51 (m, 1H),7.20-7.29 (m, 1H), 3.84-3.93 (m, 1H), 3.47-3.60 (m, 1H), 3.37-3.44 (m,1H), 3.09-3.26 (m, 2H), 1.87- 2.06 (m, 3H), 1.65-1.80 (m, 2H), 0.93-1.03(m, 3H) 459/461 GENERAL PROCEDURE A A22B02C01

1937_D1 443 GENERAL PROCEDURE A A22B02C03

1937_D2 443 GENERAL PROCEDURE A A22B02C03

1943_D1 461 GENERAL PROCEDURE A A22B02C02

1943_D2 461 GENERAL PROCEDURE A A22B02C02

1933 459/461 GENERAL PROCEDURE A A23B02C01

1939 443 GENERAL PROCEDURE A A23B02C03

1945 1H NMR (400 MHz, METHANOL- d4) δ 8.39-8.46 (m, 1H), 8.18-8.25 (m,1H), 7.54-7.64 (m, 2H), 7.44- 7.52 (m, 1H), 3.81-3.89 (m, 1H), 3.32-3.57(m, 4H), 1.79-1.98 (m, 4H), 1.55-1.64 (m, 1H), 1.02-1.09 (m, 3H) 461GENERAL PROCEDURE A A23B02C02

2096_D1 473/475 GENERAL PROCEDURE A A64B06C01

2096_D2 473/475 GENERAL PROCEDURE A A64B06C01

2097_D1 475 GENERAL PROCEDURE A A64B06C02

2097_D2 475 GENERAL PROCEDURE A A64B06C02

2098_D1 1H NMR (400 MHz, METHANOL- d4) δ 8.45-8.52 (m, 1H), 8.16-8.25(m, 1H), 7.76-7.90 (m, 1H), 7.39- 7.46 (m, 1H), 7.32-7.37 (m, 1H),7.20-7.30 (m, 1H), 4.05 (s, 4H), 3.87-3.96 (m, 1H), 3.76-3.86 (m, 1H),3.55-3.67 (m, 2H), 3.42-3.52 (m, 2H), 2.86-2.96 (m, 1H), 1.13 (d, J =6.40 Hz, 3H) 457 GENERAL PROCEDURE A A64B06C03

2098_D2 1H NMR (400 MHz, METHANOL- d4) δ 8.43-8.51 (m, 1H), 8.16-8.25(m, 1H), 7.76-7.86 (m, 1H), 7.39- 7.45 (m, 1H), 7.33-7.37 (m, 1H),7.20-7.30 (m, 1H), 4.06 (s, 4H), 3.88-4.02 (m, 3H), 3.80-3.87 (m, 1H),3.64-3.75 (m, 1H), 2.83-2.92 (m, 1H), 2.71-2.80 (m, 1H), 1.14 (d, J =6.27 Hz, 3H) 457 GENERAL PROCEDURE A A64B06C03

1835_D1 465 GENERAL PROCEDURE A A28B02C02

1835_D2 465 GENERAL PROCEDURE A A28B02C02

1836_D1 447 GENERAL PROCEDURE A A28B02C03

1836_D2 447 GENERAL PROCEDURE A A28B02C03

1837_D1 1H NMR (400 MHz, METHANOL- d4) δ 8.42-8.49 (m, 1H), 8.21-8.30(m, 1H), 7.91-8.02 (m, 1H), 7.58- 7.67 (m, 1H), 7.46-7.55 (m, 1H),7.20-7.30 (m, 1H), 4.53-4.77 (m, 1H), 3.81-3.93 (m, 1H), 3.56-3.75 (m,2H), 3.43-3.56 (m, 1H), 3.24- 3.30 (m, 1H), 2.28-2.43 (m, 1H), 1.94-2.12(m, 2H), 1.78-1.93 (m, 1H) 463/465 GENERAL PROCEDURE A A28B02C01

1837_D2 1H NMR (400 MHz, METHANOL- d4) δ 8.41-8.48 (m, 1H), 8.20-8.29(m, 1H), 7.93-8.00 (m, 1H), 7.58- 7.66 (m, 1H), 7.45-7.54 (m, 1H),7.21-7.30 (m, 1H), 4.97-5.08 (m, 1H), 4.54-4.71 (m, 1H), 4.07-4.21 (m,1H), 3.56-3.84 (m, 2H), 3.39- 3.54 (m, 1H), 3.33-3.38 (m, 1H), 2.04-2.32(m, 3H), 1.67-1.86 (m, 1H) 463/465 GENERAL PROCEDURE A A28B02C01

2093 473/475 GENERAL PROCEDURE A A65B06C01

2094 1H NMR (400 MHz, METHANOL- d4) δ 8.52-8.54 (m, 1H), 8.19-8.22 (m,1H), 7.59-7.63 (m, 2H), 7.34- 7.37 (m, 1H), 4.20-4.30 (m, 1H), 4.07 (s,1H), 3.79-3.92 (m, 4H), 3.58-3.63 (m, 2.5H), 3.14-3.50 (m, 0.5H),0.97-1.00 (m, 3H) 475 GENERAL PROCEDURE A A65B06C02

2095 457 GENERAL PROCEDURE A A65B06C03

1826_D1 465 GENERAL PROCEDURE A A26B02C02

1826_D2 465 GENERAL PROCEDURE A A26B02C02

1827_D1 447 GENERAL PROCEDURE A A26B02C03

1827_D2 447 GENERAL PROCEDURE A A26B02C03

1828_D1 1H NMR (400 MHz, METHANOL- d4) δ 8.48-8.50 (m, 1H), 8.26-8.29(m, 1H), 7.98-8.00 (m, 1H), 7.63- 7.64 (m, 1H), 7.50-7.54 (m, 1H),7.25-7.30 (m, 1H), 4.76-4.88 (m, 1H), 4.01-4.02 (m, 1H), 3.75-3.85 (m,1H), 3.71-3.74 (m, 1H), 3.46- 3.50 (m, 1H), 2.96-3.01 (m, 1H), 2.10-2.18(m, 2H), 1.78-1.85 (m, 1H), 1.54-1.60 (m, 1H) 463/465 GENERAL PROCEDUREA A26B02C01

1828_D2 463/465 GENERAL PROCEDURE A A26B02C01

1823 465 GENERAL PROCEDURE A A27B02C02

1824 447 GENERAL PROCEDURE A A27B02C03

1825 463/465 GENERAL PROCEDURE A A27B02C01

2434 1H NMR (400 MHz, METHANOL- d4) δ 8.40-8.44 (m, 1H), 8.24-8.26 (m,1H), 8.00-8.02 (m, 1H), 7.90- 7.92 (m, 1H), 7.64-7.67 (m, 1H), 7.26-7.30(m, 1H), 5.82-5.98 (m, 2H), 3.76-3.98 (m, 3H), 3.56-3.61 (m, 1H),3.28-3.30 (m, 1H), 3.00- 3.06 (m, 1H), 1.86-1.87 (m, 3H), 1.55-1.56 (m,1H) 475/477 GENERAL PROCEDURE A A68B05C01

2027 489/491 GENERAL PROCEDURE A A37B02C01

2028 473 GENERAL PROCEDURE A A37B02C03

2029 491 GENERAL PROCEDURE A A37B02C02

2014 445/447 GENERAL PROCEDURE F A02B11C01

2016 447 GENERAL PROCEDURE F A02B11C02

2049 429/431 GENERAL PROCEDURE F A53B11C01

2053 445/447 GENERAL PROCEDURE F A01B11C01

2054 459/461 GENERAL PROCEDURE F A05B11C01

2055 447/449 GENERAL PROCEDURE F A13B11C01

2056 461/463 GENERAL PROCEDURE F A35B11C01

2057 447 GENERAL PROCEDURE F A02B11C02

2061 1H NMR (400 MHz, METHANOL- d4) δ = 8.22 (s, 1H), 7.99 (d, J = 8.7Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 6.4, 10.0 Hz. 2H),3.95- 3.86 (m, 1H), 3.67 (dd, J = 4.6, 14.2 Hz, 1H), 3.54 (td, J = 6.4,13.3 Hz, 1H), 3.24-3.13 (m, 1H), 3.00 (dd, J = 8.2, 14.1 Hz, 1H), 1.97(ddd, J = 4.4, 8.1, 12.6 Hz, 1H), 1.91-1.65 (m, 3H), 1.64-1.46 (m, 2H)447 GENERAL PROCEDURE F A02B11C03

2062 461 GENERAL PROCEDURE F A05B11C02

2063 1H NMR (400 MHz, METHANOL- d4) δ = 8.25 (s, 1H), 8.01 (td, J = 2.1,8.7 Hz, 1H), 7.87 (td, J = 1.9, 7.8 Hz, 1H), 7.63 (dd, J = 6.5, 10.0 Hz,2H), 4.02 (dd, J = 5.1, 7.0 Hz, 1H), 3.94-3.84 (m, 2H), 3.80- 3.57 (m,4H), 3.32-3.27 (m, 1H), 3.21 (dd, J = 7.2, 14.2 Hz, 1H) 449 GENERALPROCEDURE F A13B11C02

2064 463 GENERAL PROCEDURE F A35B11C02

2045 1H NMR (400 MHz, METHANOL- d4) δ = 8.47 (d, J = 6.7 Hz, 1H), 8.24(br. s., 1H), 7.99 (d, J = 6.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.50(t, J = 9.2 Hz, 1H), 7.27 (t, J = 8.8 Hz, 1H), 3.62 (dd, J = 4.7, 14.2Hz, 1H), 3.51-3.39 (m, 4H), 3.14 (dd, J = 8.8, 14.0 Hz, 1H), 1.98-1.78(m, 4H), 1.75-1.51 (m, 2H), 1.42- 1.30 (m, 1H) 459/461 GENERAL PROCEDUREA A50B02C01

2046_D1 1H NMR (400 MHz, METHANOL- d4) δ = 8.46 (dd, J = 2.4, 6.7 Hz,1H), 8.24 (ddd, J = 2.4, 4.5, 8.7 Hz, 1H), 7.99 (dd, J = 2.6, 6.7 Hz,1H), 7.68-7.61 (m, 1H), 7.54-7.47 (m, 1H), 7.27 (t, J = 9.0 Hz, 1H),3.76- 3.67 (m, 1H), 3.60 (dd, J = 4.5,13.9 Hz, 1H), 3.52-3.41 (m, 1H),3.15 (dd, J = 10.2, 13.7 Hz, 1H), 1.95- 1.84 (m, 3H), 1.82-1.75 (m, 1H),1.68 (d, J = 5.0 Hz, 1H), 1.55-1.43 (m, 3H), 1.16 (d, J = 6.4 Hz, 3H)473/475 GENERAL PROCEDURE A A51B02C01

2046_D2 1H NMR (400 MHz, METHANOL- d4) δ = 8.47 (dd, J = 2.3, 6.6 Hz,1H), 8.24 (ddd, J = 2.4, 4.6, 8.6 Hz, 1H), 7.99 (dd, J = 2.6, 6.7 Hz,1H), 7.67-7.61 (m, 1H), 7.50 (dd, J = 8.8, 9.7 Hz, 1H), 7.27 (t, J = 9.0Hz, 1H), 3.71-3.62 (m, 2H), 3.44- 3.36 (m, 2H), 3.21 (dd, J = 9.1, 14.1Hz, 1H), 1.95-1.79 (m, 3H), 1.78- 1.61 (m, 2H), 1.60-1.48 (m, 1H),1.46-1.35 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H) 473/475 GENERAL PROCEDURE AA51B02C01

2076 447/449 GENERAL PROCEDURE A A67B02C01

2077 1H NMR (400 MHz, METHANOL- d4) δ = 8.48 (dd, J = 2.3, 6.7 Hz, 1H),8.30-8.23 (m, 1H), 7.98 (dd, J = 2.5, 6.7 Hz, 1H), 7.64 (td, J = 3.3,8.9 Hz, 1H), 7.52 (t, J = 9.4 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H),4.29-4.21 (m, 1H), 3.99 (td, J = 4.5, 14.1 Hz, 1H), 3.82 (dd, J = 5.5,14.9 Hz, 1H), 3.27 (dd, J = 8.1, 15.1 Hz, 2H), 3.04 (dd, J = 4.3, 15.1Hz, 1H), 2.89- 2.76 (m, 3H) 463/465 GENERAL PROCEDURE A A43B02C01

2159 461/463 GENERAL PROCEDURE A A38B02C01

2160 475/477 GENERAL PROCEDURE A A39B02C01

2161 487/489 GENERAL PROCEDURE A A42B02C01

2162 491/493 GENERAL PROCEDURE A A41B02C01

2163 505/507 GENERAL PROCEDURE A A40B02C01

2164 473/475 GENERAL PROCEDURE A A38B06C01

2165 475 GENERAL PROCEDURE A A38B06C02

2166 457 GENERAL PROCEDURE A A38B06C03

2167 487/489 GENERAL PROCEDURE A A39B06C01

2168 489 GENERAL PROCEDURE A A39B06C02

2169 471 GENERAL PROCEDURE A A39B06C03

2173 503/505 GENERAL PROCEDURE A A41B06C01

2174 505 GENERAL PROCEDURE A A41B06C02

2175 487 GENERAL PROCEDURE A A41B06C03

2176 517/519 GENERAL PROCEDURE A A40B06C01

2177 519 GENERAL PROCEDURE A A40B06C02

2178 501 GENERAL PROCEDURE A A40B06C03

2197 481/483 GENERAL PROCEDURE A A45B02C01

2198 1H NMR (400 MHz, METHANOL- d4) δ = 8.47 (dd, J = 2.4, 6.7 Hz, 1H),8.27 (ddd, J = 2.4, 4.6, 8.5 Hz, 1H), 7.84 (ddd, J = 2.6, 7.4, 12.8 Hz,1H), 7.56-7.42 (m, 2H), 7.34- 7.23 (m, 1H), 4.05-3.89 (m, 2H), 3.80-3.65(m,1H), 3.58-3.47 (m, 1H), 3.20 (ddd, J = 5.8, 7.7, 13.3 Hz, 1H),2.07-1.76 (m, 4H) 465 GENERAL PROCEDURE A A45B02C03

2199 1H NMR (400 MHz, METHANOL- d4) δ = 8.46 (dd, J = 2.4, 6.7 Hz, 1H),8.26 (ddd, J = 2.4, 4.6, 8.6 Hz, 1H), 7.61 (dd. J = 6.4, 10.0 Hz, 2H),7.52 (dd, J = 8.7, 10.0 Hz, 1H), 4.05- 3.88 (m, 2H), 3.79-3.65 (m, 1H),3.58-3.47 (m, 1H), 3.19 (ddd, J = 5.8, 7.6, 13.3 Hz, 1H), 2.10-1.74 (m,4H) 483 GENERAL PROCEDURE A A45B02C02

2200 ¹HNMR (400 MHz, METHANOL) δ = 8.44 (dd, J = 2.3, 6.5 Hz, 1H), 8.23(m, 1H), 7.96 (dd, J = 2.5, 6.8 Hz, 1H), 7.65-7.57 (m, 1H), 7.49 (t, J =9.3 Hz, 1H), 7.25 (t, J = 8.9Hz, 1H), 4.03-3.94 (m, 1H), 3.62- 3.47 (m,4H), 2.49-2.32 (m, 1H), 2.28-2.11 (m, 1H), 2.08-1.87 (m, 2H) 481/483GENERAL PROCEDURE A A44B02C01

2201 ¹HNMR (400MHz, METHANOL) δ = 8.44 (dd, J = 2.1, 6.7 Hz, 1H),8.28-8.20 (m, 1H), 7.83 (m, 1H), 7.53-7.38 (m, 2H), 7.32-7.20 (m, 1H),3.99 (d, J = 7.8 Hz, 1H), 3.53 (br.s., 4H), 2.46-2.33 (m, 1H), 2.27-2.14(m, 1H), 2.06-1.92 (m, 2H) 465/467 GENERAL PROCEDURE A A44B02C03

2202 483/485 GENERAL PROCEDURE A A44B02C02

2221 1H NMR (400 MHz, METHANOL- d4) δ = 8.43 (s, 1H), 8.27 (dd, J = 1.8,8.0 Hz, 1H), 8.00 (dd, J = 2.6, 6.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H),7.66 (ddd, J = 2.6, 4.1, 9.0 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 5.91 (s,1H), 5.79 (s, 1H), 4.04-3.89 (m, 2H), 3.86-3.71 (m, 1H), 3.54-3.43 (m,1H), 3.23 (ddd, J = 5.8, 7.7, 13.4 Hz, 1H), 2.10-1.72 (m, 4H) 495/497GENERAL PROCEDURE A A45B05C01

2222 479 GENERAL PROCEDURE A A45B05C03

2223 497 GENERAL PROCEDURE A A45B05C02

2224 ¹HNMR (400 MHz, METHANOL-d₄) δ = 8.38 (s, 1H), 8.23 (d, J = 8.0 Hz,1H), 7.98 (dd, J = 2.5, 6.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.67-7.60(m, 1H), 7.26 (t, J = 9.0 Hz, 1H), 5.92 (s, 1H), 5.81 (s, 1H), 4.05-3.94 (m, 1H), 3.64-3.45 (m, 4H), 2.45-2.29 (m, 1H), 2.25-2.09 (m, 1H),2.08-1.90 (m, 2H) 495/497 GENERAL PROCEDURE A A44B05C01

2225 479/481 GENERAL PROCEDURE A A44B05C03

2226 497/499 GENERAL PROCEDURE A A44B05C02

2421 473/475 GENERAL PROCEDURE A A46B02C01

2422 475 GENERAL PROCEDURE A A46B02C02

2425 1H NMR (400 MHz, METHANOL- d4) δ = 8.43 (dd, J = 2.3, 6.6 Hz, 1H),8.24 (ddd, J = 2.4, 4.6, 8.6 Hz, 1H), 7.98 (dd, J = 2.6, 6.7 Hz, 1H),7.66-7.60 (m, 1H), 7.49 (dd, J = 8.8, 9.8 Hz, 1H), 7.26 (t, J = 9.0 Hz,1H), 3.58-3.49 (m, 1H), 3.45- 3.34 (m, 4H), 2.03-1.94 (m, 1H), 1.91-1.78(m, 2H), 1.50 (ddd, J = 4.6, 8.0, 15.3 Hz, 1H), 1.01 (d, J = 19.1 Hz,6H) 473/475 GENERAL PROCEDURE A A47B02C01

2426 475 GENERAL PROCEDURE A A47B02C02

2427 487/489 GENERAL PROCEDURE A A47B05C01

2428 489 GENERAL PROCEDURE A A47B05C02

2529 475 GENERAL PROCEDURE A A48B02C02

2530 473/475 GENERAL PROCEDURE A A48B02C01

2531 489 GENERAL PROCEDURE A A48B05C02

2532 487/489 GENERAL PROCEDURE A A48B05C01

2537_D1 463 GENERAL PROCEDURE A A65B02C02

2537_D2 463 GENERAL PROCEDURE A A65B02C02

2538_D1 461 GENERAL PROCEDURE A A65B02C01

2538_D2 461 GENERAL PROCEDURE A A65B02C01

2539_D1 477/499 GENERAL PROCEDURE A A65B05C02

2539_D2 477/499 GENERAL PROCEDURE A A65B05C02

2540_D1 ¹H NMR (400 MHz, MeOD) δ 8.56 (S, 1H), 8.26-8.24 (dd, 1H), 8.00-7.97 (dd, 1H), 7.91-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.28-7.24 (t, 1H),5.93-5.92 (m, 1H), 5.81-5.80 (m, 1H), 4.19-4.14 (m, 1H), 3.97- 3.91 (m,2H), 3.78-3.67 (m, 2H), 3.48-3.39 (m, 2H), 3.29-3.23 (m, 1H), 1.04-1.03(d, 3H). 475 GENERAL PROCEDURE A A65B05C01

2540_D2 475 GENERAL PROCEDURE A A65B05C01

2541 ¹H NMR (400 MHz, MeOD) δ 8.52- 8.50 (dd, 1H), 8.25-8.23(m, 1H),7.61-7.57 (m, 2H), 7.50- 7.47 (m, 1H), 3.94-3.89 (m, 3H), 3.60-3.47 (m,4H), 1.41 (s, 3H), 1.28 (s, 3H). 477 GENERAL PROCEDURE A A66B02C02

2542 ¹H NMR (400 MHz, MeOD) δ 8.53- 8.51 (dd, 1H), 8.25-8.22 (m, 1H),7.96-7.94 (m, 1H), 7.63- 7.59 (m, 1H), 7.49-7.45 (t, 1H), 7.26-7.22 (t,1H), 3.99-3.89 (m, 2H), 3.83-3.77 (m, 1H), 3.63-3.45 (m, 4H), 1.41 (s,3H), 1.28 (s, 3H). 475 GENERAL PROCEDURE A A66B02C01

2543 ¹H NMR (400 MHz, MeOD) δ 8.43- 8.46 (m, 1H), 8.23-8.25 (m, 1H),7.80-7.86 (m, 1H), 7.44- 7.53 (m, 2H), 7.26-7.31 (m, 1H), 4.41-4.53 (m,1H), 3.77-3.81 (m, 1H), 3.41-3.72 (m, 4H), 1.73- 2.25 (m, 4H). 447GENERAL PROCEDURE A A66B05C02

2544 463/465 GENERAL PROCEDURE A A66B05C01

2545 475 GENERAL PROCEDURE A A49B02C02

2546 473/475 GENERAL PROCEDURE A A49B02C01

2535 489 GENERAL PROCEDURE A A49B05C02

2536 487/489 GENERAL PROCEDURE A A49B05C01

2494_D1 489/491 GENERAL PROCEDURE A A51B02C01

2494_D2 489/491 GENERAL PROCEDURE A A51B02C01

2433_D1 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.69 (s, 1 H) 8.38 (dd, J = 6.78,2.26 Hz, 1 H), 8.30 (ddd, J = 8.66, 4.64, 2.26 Hz, 1 H), 8.03 (dd, J =6.84, 2.57 Hz, 1 H), 7.65-7.73 (m, 2 H), 7.44 (t, J = 9.16 Hz, 1 H),4.93 (d, J = 4.27 Hz, 2 H), 3.68- 3.82 (m, 4 H), 2.66-2.75 (m, 2 H),1.67 (br. s., 4 H). 461/463 GENERAL PROCEDURE A A68B02C01 Separated byPre-HPLC for mixture

2433_D2 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.69 (s, 1 H), 8.38 (dd, J =6.78, 2.26 Hz, 1 H), 8.30 (ddd, J = 8.66, 4.64, 2.26 Hz, 1 H), 8.03 (dd,J = 6.84, 2.57 Hz, 1 H), 7.65-7.73 (m, 2 H), 7.44 (t, J = 9.16 Hz, 1 H),4.93 (d, J = 4.27 Hz, 2H), 3.68- 3.82 (m, 4 H), 2.66-2.75 (m, 2 H), 1.67(br, 4 H). 461/463 GENERAL PROCEDURE A A68B02C01 Separated by Pre-HPLCfor mixture in the first synthesis; Made from A68_Cis in the second run.

2617_D1 ¹H NMR (400 MHz, METHANOL- d₄) ppm 8.45 (dd, J = 6.59, 2.32 Hz,1 H), 8.24 (ddd, J = 8.66, 4.64, 2.38 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.50(dd, J = 10.04, 8.66 Hz, 1 H), 3.92- 4.01 (m, 2 H), 3.87 (dd, J = 14.31,5.90 Hz, 2 H), 2.84 (dd, J = 13.80, 8.41 Hz, 2 H), 1.80-1.91 (m, 4 H),463 GENERAL PROCEDURE A A68B02C02 Made from A68_Trans

2617_D2 ¹H NMR (400 MHz, METHANOL- d₄) ppm 8.45 (dd,J = 6.59, 2.32 Hz, 1H), 8.24 (ddd, J = 8.66, 4.64, 2.38 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.50(dd, J = 10.04, 8.66 Hz, 1 H), 3.92- 4.01 (m, 2 H), 3.87 (dd, J = 14.31,5.90 Hz, 2 H), 2.84 (dd, J = 13.80, 8.41 Hz, 2 H), 1.80-1.91 (m, 4 H),463 GENERAL PROCEDURE A A68B02C02 Made from A68_Cis

2619_D2 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.69 (s, 1 H) 8.38 (dd, J = 6.78,2.26 Hz, 1 H) 8.27-8.34 (m, 1 H) 8.04 (dd, J = 6.90, 2.51 Hz, 1 H)7.66-7.74 (m, 2 H) 7.44 (t, J = 9.10 Hz, 1 H) 4.99 (d, J = 4.27 Hz, 1 H)4.90 (br.s., 1 H) 3.67-3.80 (m, 2 H) 3.59 (dd, J = 13.80, 5.27 Hz, 1 H)3.20 (dd, J = 14.68, 7.03 Hz, 1 H) 2.94 (dd, J = 13.80, 8.03 Hz, 1 H)1.81-1.93 (m, 1 H) 1.66-1.78 (m, 3 H) 503/505 GENERAL PROCEDURE HA67B02C01 Made from 2433_D2

2618_D1 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.82 (s, 1 H), 8.37 (dd, J =6.65, 2.26 Hz, 1 H), 8.30 (ddd, J = 8.56, 4.61, 2.38 Hz, 1 H), 7.65-7.75(m, 3 H), 4.96 (d, J = 4.14 Hz, 1 H), 4.85 (dd, J = 7.15, 4.02 Hz, 1 H),3.81 (br, 1 H), 3.72 (dd, J = 14.87, 3.70 Hz, 1 H), 3.61 (dd, J = 13.87,5.33 Hz, 1 H), 3.40 (dd, J = 15.12, 3.95 Hz, 1 H), 2.79 (dd, J = 14.05,8.16 Hz, 1 H), 1.86-2.04 (m, 5 H), 1.41-1.62 (m, 2 H). 505 GENERALPROCEDURE H A67B02C02 Made from 2617_D1

2618_D2 ¹H NMR (400 MHz, METHANOL- d₄) ppm 8.45 (dd, J = 6.65, 2.26 Hz,1 H), 8.24 (ddd, J = 8.66, 4.64, 2.38 Hz, 1 H), 7.54-7.64 (m, 2 H) 7.50(dd, J = 9.91, 8.78 Hz, 1 H), 4.99- 5.08 (m, 1 H), 3.88-3.97 (m, 1 H)3.76 (td, J = 15.25, 5.40 Hz, 2 H), 3.27 (d, J = 6.65 Hz, 1 H), 3.05(dd, J = 14.18, 7.78 Hz, 1 H), 1.95-2.08 (m, 4 H), 1.80-1.92 (m, 3 H).505 GENERAL PROCEDURE H A67B02C02 Made from 2617_D2

1916 459/461 GENERAL PROCEDURE A A02B05C01

1819 459/461 GENERAL PROCEDURE A A02B05C01

1829-2 475 GENERAL PROCEDURE A A06B05C02

1983 461/463 GENERAL PROCEDURE A A13B05C01

2625_D2 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.80 (s, 1 H) 8.26-8.37 (m, 2 H)7.65- 7.76 (m, 3 H) 4.89 (d, J = 3.89 Hz, 2 H) 3.54-3.63 (m, 2 H)3.43-3.51 (m, 2 H) 1.86-2.04 (m, 8 H) 1.73-1.85 (m, 2 H)   547.1 GENERALPROCEDURE H A68B02C02 Made from 2617_D2

2626_D2 ¹H NMR (400 MHz, DMSO-d₆) ppm 10.70 (s, 1H), 8.39-8.27 (m, 2H),8.04 (dd, J = 2.5, 6.8 Hz, 1H), 7.74-7.66 (m, 2H), 7.44 (t, J = 9.1 Hz,1H), 4.89 (d, J = 4.0 Hz, 2H), 3.63-3.53 (m, 2H), 3.51-3.42 (m, 2H),2.05-1.86 (m, 8H), 1.86-1.73 (m, 2H) 545.1/547.1 GENERAL PROCEDURE HA68B02C01 Made from 2433_D2

2632 ¹H NMR (400 MHz, MeOD) δ 8.49 (dd, J = 6.65, 2.13 Hz, 1 H),8.21-8.31 (m, 1 H), 8.02 (dd, J = 6.65, 2.64 Hz, 1 H), 7.61- 7.70 (m, 1H), 7.52 (t, J = 9.29 Hz, 1 H), 7.27 (t, J = 8.91 Hz, 1 H), 4.58 (br.s., 1 H), 3.87-4.13 (m, 3 H), 3.03 (dd, J = 14.56, 7.78 Hz, 1 H), 2.88(dd, J = 13.80, 9.03 Hz, 1 H), 2.10 (dd, J = 11.67, 6.15 Hz, 1 H),1.80-2.01 (m, 3 H) 541/543 GENERAL PROCEDURE I A68B02C01 Made from2433_D2

2634 ¹H NMR (400 MHz, MeOD) δ 9.14 (s, 1 H), 8.51 (d, J = 4.52 Hz, 1H),8.23 (brs, 1 H), 8.04 (dd, J = 6.59, 2.45 Hz, 1 H), 7.63- 7.75 (m, 1 H),7.50 (t, J = 9.32 Hz, 1 H), 7.25 (t, J = 8.95 Hz, 1 H), 4.49 (brs, 1 H),3.79-4.07 (m, 5 H), 3.70 (t, J = 8.85 Hz, 1 H), 3.34-3.47 (m, 2 H)527/529 GENERAL PROCEDURE I A13B02C01 Made from 1893

or pharmaceutically acceptable salts thereof.

In yet another embodiment of Formula I provided herein, the compound ofFormula V, or a pharmaceutically acceptable salt thereof, is selectedfrom:

TABLE 2

1763_E1

1763_E2

1765

1766_E1

1766_E2

1819

1821_D1

1821_D2

1822_D1

1822_D2

1826_D2

1829_D1

1829_D2

1829-2

1893_E1

1893_E2

1895

1916

1983

1987

1989

2202

2433_D1

2433_D2

2492

2505

2550

2617_D2

2618_D1

2618_D2

2619_D2

2625_D2

2626_D2

2632

2634

or pharmaceutically acceptable salts thereof.

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the R or Sconfiguration. In one embodiment, compounds described herein are presentin optically active or racemic forms. It is to be understood that thecompounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In oneembodiment, a mixture of one or more isomer is utilized as thetherapeutic compound described herein. In another embodiment, compoundsdescribed herein contain one or more chiral centers. These compounds areprepared by any means, including stereoselective synthesis,enantioselective synthesis and/or separation of a mixture of enantiomersand/or diastereomers. Resolution of compounds and isomers thereof isachieved by any means including, by way of non-limiting example,chemical processes, enzymatic processes, fractional crystallization,distillation, and chromatography.

In one embodiment, the compounds of the invention may exist astautomers. All tautomers are included within the scope of the compoundspresented herein.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug and/or substrate tissue distributionstudies. In another embodiment, substitution with heavier isotopes suchas deuterium affords greater metabolic stability (for example, increasedin vivo half-life or reduced dosage requirements). In yet anotherembodiment, substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds are prepared by any suitable method or by processes using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

In one embodiment, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (allof which are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

In one embodiment, reactive functional groups, such as hydroxyl, amino,imino, thio or carboxy groups, are protected in order to avoid theirunwanted participation in reactions. Protecting groups are used to blocksome or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In another embodiment, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

In one embodiment, protective groups are removed by acid, base, reducingconditions (such as, for example, hydrogenolysis), and/or oxidativeconditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are used to protect carboxy andhydroxy reactive moieties in the presence of amino groups protected withCbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties areblocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl, in the presence of amines that are blocked with acidlabile groups, such as t-butyl carbamate, or with carbamates that areboth acid and base stable but hydrolytically removable.

METHODS OF THE INVENTION

The invention provides a method of treating an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention also provides a method of eradicating an HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of theinvention.

The invention also provides a method of reducing viral load associatedwith an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention further provides a method of reducing reoccurrence of anHBV infection in an individual in need thereof, comprising administeringto the individual a therapeutically effective amount of a compound ofthe invention.

The invention also providess a method of reducing an adversephysiological impact of an HBV infection in an individual in needthereof, comprising administering to the individual a therapeuticallyeffective amount of a compound of the invention.

The invention further provides a method of reducing, slowing, orinhibiting an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention also provides a method of inducing remission of hepaticinjury from an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of the invention.

The invention further provides a method of reducing the physiologicalimpact of long-term antiviral therapy for HBV infection in an individualin need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention further provides a method of prophylactically treating anHBV infection in an individual in need thereof, wherein the individualis afflicted with a latent HBV infection, comprising administering tothe individual a therapeutically effective amount of a compound of theinvention.

In one embodiment, the methods described herein further compriseadministering at least one additional therapeutic agent selected fromthe group consisting of nucleotide/nucleoside analogs, entry inhibitors,fusion inhibitors, and any combination of these or other antiviralmechanisms. In another embodiment, the compound of the invention and theat least one additional therapeutic agent are co-formulated. In yetanother embodiment, the compound of the invention and the at least oneadditional therapeutic agent are co-administered.

In one embodiment, the individual is refractory to other therapeuticclasses of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viralentry inhibitors, viral maturation inhibitors, literature-describedcapsid assembly modulators, antiviral compounds of distinct or unknownmechanism, and the like, or combinations thereof). In anotherembodiment, the method of the invention reduces viral load in anindividual suffering from an HBV infection to a greater extent or at afaster rate compared to the extent that other therapeutic classes of HBVdrugs reduce viral load in the individual.

In one embodiment, the administering of a compound of the invention, ora pharmaceutically acceptable salt thereof, allows for administering ofthe at least one additional therapeutic agent at a lower dose orfrequency as compared to the administering of the at least oneadditional therapeutic agent alone that is required to achieve similarresults in prophylactically treating an HBV infection in an individualin need thereof.

In one embodiment, the administering of a compound of the invention, ora pharmaceutically acceptable salt thereof, reduces the viral load inthe individual to a greater extent or at a faster rate compared to theadministering of a compound selected from the group consisting of a HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and any combination thereof.

In one embodiment, the method of the invention reduces viral load in anindividual suffering from an HBV infection, thus allowing lower doses orvarying regimens of combination therapies to be used.

In one embodiment, the method of the invention causes a lower incidenceof viral mutation and/or viral resistance compared to other classes ofHBV drugs, thereby allowing for long term therapy and minimizing theneed for changes in treatment regimens.

In one embodiment, the administering of a compound the invention, or apharmaceutically acceptable salt thereof, causes a lower incidence ofviral mutation and/or viral resistance than the administering of acompound selected from the group consisting of a HBV polymeraseinhibitor, interferon, viral entry inhibitor, viral maturationinhibitor, distinct capsid assembly modulator, antiviral compounds ofdistinct or unknown mechanism, and combination thereof.

In one embodiment, the method of the invention increases theseroconversion rate beyond that of current treatment regimens.

In one embodiment, the method of the invention increases and/ornormalizes and/or restores normal health, elicits full recovery ofnormal health, restores life expectancy, and/or resolves the viralinfection in the individual in need thereof.

In one embodiment, the method of the invention eradicates HBV from anindividual infected with HBV, thereby obviating the need for long termand/or life-long treatment, or shortening the duration of treatment,and/or allowing for reduction in dosing of other antiviral agents.

In another embodiment, the method of the invention further comprisesmonitoring the HBV viral load of the subject, and wherein the method iscarried out for a period of time such that the HBV virus isundetectable.

Accordingly, in one embodiment, provided herein is a method of treatingan HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of FormulaII, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of FormulaIII, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of FormulaIV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound of FormulaV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1763_E1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1763_E2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1765, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1766_E1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1766_E2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1768, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1769, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1819, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1820, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1821, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1821_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1821_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1822_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1822_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1826_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1829_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1829_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1829-2, ora pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1890, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1891, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1892, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1893, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1893_E1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1893_E2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1894, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1895, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1909, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1910, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1914, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1915, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1916, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1917, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1919, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1938, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1944, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1975, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1977, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1979, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1980, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1981, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1983, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1986, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1987, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 1989, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2002, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2004, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2007, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2024, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2033, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2114_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2114_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2121, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2123, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2199, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2202, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2205, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2206, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2433_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2433_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2492, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2505, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2547, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2548, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2550, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2617_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2618_D1,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2618_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2619_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2625_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2626_D2,or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2632, or apharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of compound 2634, or apharmaceutically acceptable salt thereof.

Combination Therapies

The compounds of the present invention are intended to be useful incombination with one or more additional compounds useful for treatingHBV infection. These additional compounds may comprise compounds of thepresent invention or compounds known to treat, prevent, or reduce thesymptoms or effects of HBV infection. Such compounds include but are notlimited to HBV polymerase inhibitors, interferons, viral entryinhibitors, viral maturation inhibitors, literature-described capsidassembly modulators, reverse transcriptase inhibitor, a TLR-agonist, andother agents with distinct or unknown mechanisms that affect the HBVlife cycle and/or affect the consequences of HBV infection.

In non-limiting examples, the compounds of the invention may be used incombination with one or more drugs (or a salt thereof) selected from thegroup consisting of

HBV reverse transcriptase inhibitors, and DNA and RNA polymeraseinhibitors, including but not limited to: lamivudine (3TC, Zeffix,Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir),adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovirdisoproxil fumarate (Viread, TDF or PMPA);

interferons, including but not limited to interferon alpha (IFN-α),interferon lambda (IFN-λ), and interferon gamma (IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as, but notlimited to BAY 41-4109;

reverse transcriptase inhibitor;

a TLR-agonist; and

agents of distinct or unknown mechanism, such as but not limited toAT-61((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide),AT-130((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide),and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon.The term “interferon” or “IFN” refers to any member the family of highlyhomologous species-specific proteins that inhibit viral replication andcellular proliferation, and modulate immune response. Human interferonsare grouped into three classes; Type I, which include interferon-alpha(IFN-α), interferon-beta (IFN-β), and interferon-omega (IFN-ω), Type II,which includes interferon-gamma (IFN-γ), and Type III, which includesinterferon-lambda (IFN-λ). Recombinant forms of interferons that havebeen developed and are commercially available are encompassed by theterm “interferon” as used herein. Subtypes of interferons, such aschemically modified or mutated interferons, are also encompassed by theterm “interferon” as used herein. Chemically modified interferonsinclude pegylated interferons and glycosylated interferons. Examples ofinterferons include, but are not limited to, interferon-alpha-2a,interferon-alpha-2b, interferon-alpha-n1, interferon-beta-1a,interferon-beta-1b, interferon-lamda-1, interferon-lamda-2, andinterferon-lamda-3. Examples of pegylated interferons include pegylatedinterferon-alpha-2a and pegylated interferson alpha-2b.

Accordingly, in one embodiment, the compounds of Formula I, Ia, Ib, II,III, IV, V, Vx, or Va can be administered in combination with aninterferon selected from the group consisting of interferon alpha(IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), andinterferon gamma (IFN-γ). In one specific embodiment, the interferon isinterferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. Inanother specific embodiment, the interferon-alpha-2a orinterferon-alpha-2b is pegylated. In a preferred embodiment, theinterferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS).

In another embodiment, the additional therapeutic agent is selected fromimmune modulator or immune stimulator therapies, which includesbiological agents belonging to the interferon class.

Further, the additional therapeutic agent may be an agent of distinct orunknown mechanism including agents that disrupt the function of otheressential viral protein(s) or host proteins required for HBV replicationor persistence.

In another embodiment, the additional therapeutic agent is an antiviralagent that blocks viral entry or maturation or targets the HBVpolymerase such as nucleoside or nucleotide or non-nucleos(t)idepolymerase inhibitors. In a further embodiment of the combinationtherapy, the reverse transcriptase inhibitor and/or DNA and/or RNApolymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA,Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine,Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir,ganciclovir, valganciclovir, Tenofovir, Adefovir, cidofovir, Efavirenz,Nevirapine, Delavirdine, or Etravirine.

In one embodiment, the additional therapeutic agent is a TLR modulatoror a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. In furtherembodiment of the combination therapy, the TLR-7 agonist is selectedfrom the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In any of the methods provided herein, the method may further compriseadministering to the individual at least one HBV vaccine, a nucleosideHBV inhibitor, an interferon or any combination thereof. In anembodiment, the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B,ELOVAC B, GENEVAC-B, or SHANVAC B.

In another aspect, provided herein is method of treating an HBVinfection in an individual in need thereof, comprising reducing the HBVviral load by administering to the individual a therapeuticallyeffective amount of a compound of the invention alone or in combinationwith a reverse transcriptase inhibitor; and further administering to theindividual a therapeutically effective amount of HBV vaccine. Thereverse transcriptase inhibitor may be one of Zidovudine, Didanosine,Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

For any combination therapy described herein, synergistic effect may becalculated, for example, using suitable methods such as theSigmoid-E_(max) equation (Holford & Scheiner, 19981, Clin.Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe &Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and themedian-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimentaldata to generate a corresponding graph to aid in assessing the effectsof the drug combination. The corresponding graphs associated with theequations referred to above are the concentration-effect curve,isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations

In another aspect, provided herein is pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Inone embodiment, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a compound of theinvention and a pharmaceutically acceptable carrier.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg toabout 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg toabout 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80mg to about 500 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound of the invention is fromabout 1 mg to about 2,500 mg. In some embodiments, a dose of a compoundof the invention used in compositions described herein is less thanabout 10,000 mg, or less than about 8,000 mg, or less than about 6,000mg, or less than about 5,000 mg, or less than about 3,000 mg, or lessthan about 2,000 mg, or less than about 1,000 mg, or less than about 500mg, or less than about 200 mg, or less than about 50 mg. Similarly, insome embodiments, a dose of a second compound (i.e., another drug forHBV treatment) as described herein is less than about 1,000 mg, or lessthan about 800 mg, or less than about 600 mg, or less than about 500 mg,or less than about 400 mg, or less than about 300 mg, or less than about200 mg, or less than about 100 mg, or less than about 50 mg, or lessthan about 40 mg, or less than about 30 mg, or less than about 25 mg, orless than about 20 mg, or less than about 15 mg, or less than about 10mg, or less than about 5 mg, or less than about 2 mg, or less than about1 mg, or less than about 0.5 mg, and any and all whole or partialincrements thereof.

In one embodiment, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention, aloneor in combination with a second pharmaceutical agent; and instructionsfor using the compound to treat, prevent, or reduce one or more symptomsof HBV infection in a patient.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients that are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose and/or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizingand/or dispersing agents may be used.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Materials:

Unless otherwise noted, all starting materials and resins were obtainedfrom commercial suppliers and used without purification.

Region A:

Region B:

Region C:

Part I Intermediate Synthesis (Regions A, B & C)

1 Preparation of Region A Intermediates

1.1 Preparation of A01/02

1.1.1 Preparation of Compound 2 and 3

To a solution of Compound 1 (5.0 g, 21.5 mmol) and ethyl 2-diazoacetate(3.2 g, 28.1 mmol) in THF (100 mL) was added BF₃-Et₂O (2.7 mL, 21.5mmol) at −78° C. under N₂. The reaction mixture was stirred at −78° C.for 1.5 h, then warmed to 28° C. slowly and stirred for 1.5 h. Theresulting mixture was quenched with NaHCO₃ (sat.) and extracted with EA(300 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to give a crude product, which was purified by flash columnchromatography to give a mixture of Compound 2 and 3 (3.4 g, 50%). LCMS:320.0 [M+1].

1.1.2 Preparation of Compound 4 and 5

To a mixture of compound 2 and 3 (1 g, 3.1 mmol) dissolved MeOH/H₂O (10mL/2 mL) was added KOH (0.53 g, 9.3 mmol), and heated to 55° C. for 2 h.The mixture was diluted with EA (80 mL) and washed with brine (60 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo togive a crude product, which was purified by flash column chromatographyto give Compound 4 (0.32 g, 42%) and Compound 5 (0.22 g, 29%). LCMS:248.0 [M+1]. Compound 4 ¹H NMR (400 MHz, CDCl3) δ 7.34-7.40 (m, 5H),5.16-5.21 (m, 2H), 4.06-4.11 (m, 2H), 3.46-3.49 (m, 2H), 2.51-2.55 (m,2H), 1.63-1.78 (m, 4H). Compound 5 ¹H NMR (400 MHz, CDCl3) δ 7.34-7.39(m, 5H), 5.14 (s, 2H), 3.62-3.69 (m, 4H), 2.62-2.71 (m, 4H), 2.75-2.81(m, 2H).

1.1.3 Preparation of Compound 6

To a solution of compound 4 (0.32 g, 1.3 mmol) in EtOH (20 mL) was addedNaBH₄ (74.2 mg, 1.9 mmol) at 0° C., and the mixture was stirred at 25°C. for 2 h. The resulting mixture was quenched with NH₄Cl (sat.) andextracted with EA (80 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (0.24 g, 74%).LCMS: 250.0 [M+1].

1.1.4 Preparation of Compound A01

To a solution of Compound 6 (0.25 g, 1.0 mmol) in MeOH (25 mL) was addedPd(OH)₂/C (50 mg). The mixture was hydrogenated at 25° C. for 16 h under25 Psi pressure. The catalyst was filtered and the filtrate wasconcentrated to give the crude product, which was used in the next stepdirectly (0.1 g, 87%).

1.1.5 Preparation of Compound 7

To a solution of compound 5 (0.32 g, 1.3 mmol) in EtOH (20 mL) was addedNaBH₄ (74.2 mg, 1.9 mmol) at 0° C., and the mixture was stirred at 25°C. for 2 h. The resulting mixture was quenched with NH₄Cl (sat.) andextracted with EA (80 mL). The organic layer was dried and concentratedto give the crude product, which was purified by flash columnchromatography to give the desired product (0.24 g, 74%). LCMS: 250.0[M+1].

1.1.6 Preparation of Compound A02

To a solution of Compound 5 (0.25 g, 1.0 mmol) in MeOH (25 mL) was addedPd(OH)₂/C (50 mg). The mixture was hydrogenated at 25° C. for 16 h under25 psi pressure. The catalyst was filtered and the filtrate wasconcentrated to give the crude product, which was used in the next stepdirectly (0.1 g, 87%).

1.2 Preparation of A03/04

1.2.1 Preparation of Compound 2

To a solution of Compound 1 (0.8 g, 3.2 mmol) in DCM (30 mL) was addedDAST (1.1 g, 6.5 mmol) at −78° C. under N₂. The reaction mixture wasstirred at −78° C. for 2 h and then warmed to 28° C. for 2 h. Theresulting mixture was quenched with NaHCO₃(sat.) and extracted with DCM(30 mL). The organic layer was dried and concentrated to give the crudeproduct, which was purified by flash column chromatography PE:EA(30:1)to give the desired product (0.6 g, 74%). LCMS: 252.0 [M+1].

1.2.2 Preparation of Compound A03

To a solution of Compound 2 (0.6 g, 2.4 mmol) in MeOH (25 mL) was addedPd(OH)₂/C (100 mg). The mixture was hydrogenated at 25° C. for 16 hunder H₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the crude product (0.3 g), which was used in thenext step directly.

Amine A04 was prepared through the same procedure with amine A03 frombenzyl 4-hydroxyazepane-1-carboxylate.

1.3 Preparation of A05/06

1.3.1 Preparation of Compound 2

To a solution of CH₃MgBr (14.2 mmol) in THF (10 mL) was added Compound 1(0.7 g, 2.8 mmol) in THF (20 mL) at 0° C. under N₂. The reaction mixturewas stirred at 0° C. for 2 h. The resulting mixture was quenched withNH₄Cl (sat.) and extracted with EtOAc (30 mL). The organic layer wasdried and concentrated in vacuo to give the crude product, which waspurified by flash column chromatography PE:EA(10:1) to give the desiredproduct (0.2 g, 27%). LCMS: 264 [M+1].

1.3.2 Preparation of Compound A05

To a solution of Compound 2 (0.34 g, 1.3 mmol) in MeOH (25 mL) was addedPd(OH)₂/C (50 mg). The mixture was hydrogenated at 25° C. for 16 h underH₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the crude product, which was used in the next stepdirectly (0.16 g, 94%).

Amine A06 was prepared through the same procedure with amine A03 frombenzyl 4-oxoazepane-1-carboxylate.

1.4 Preparation of A07/08

1.4.1.1 Preparation of Compound 3 and 3′

A mixture of compound 3 and 3′ was prepared with the same procedure as1.1.1.

1.4.1.2 Preparation of Compound 4 and Compound 4′

To a suspension of NaH (338 mg, 8.5 mmol) in THF (30 mL) was added asolution of a mixture of Compound 3 and Compound 3′ (2.7 g, 8.5 mmol) inTHF (30 mL) at 0° C. under N₂, and stirred at rt for 0.5 h. A solutionof Select F (2.7 g, 8.5 mmol) in DMF (15 mL) was added dropwise. Thereaction mixture was stirred at r.t. for 3 h. The resulting mixture wasquenched with NH₄Cl and extracted with EA (200 mL). The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive the crude product, which was purified by flash columnchromatography to give Compound 4 (1.0 g, 35%) and Compound 4′(0.9 g,32%). Compound 4: ¹H NMR (400 MHz, CDCl₃) δ=7.28-7.39 (m, 5H), 5.18 (s,2H), 4.40-4.68 (m, 1H), 4.11-4.39 (m, 3H), 3.45-3.63 (m, 1H), 3.21-3.38(m, 1H), 1.85-2.45 (m, 4H), 1.26-1.30 (m, 3H). Compound 4′: ¹H NMR (400MHz, CDCl₃) δ=7.28-7.40 (m, 5H), 5.14-5.18 (m, 2H), 4.24-4.47 (m, 4H),3.88-4.00 (m, 1H), 3.09-3.25 (m, 1H), 2.85-2.91 (m, 2H), 1.92-1.95 (m,2H), 1.27-1.35 (m, 3H).

1.4.1.3 Preparation of Compound 5

A mixture of compound 4 (0.72 g, 2.1 mmol) and KOH (0.18 g, 3.2 mmol) inMeOH/H₂O (10 mL/2 mL) was heated to 55° C. for 2 h. The mixture wasextracted with EA (80 mL) and washed with brine (60 mL). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to give the crudeproduct, which was used in the next step directly (0.54 g, crude). LCMS:266.0 [M+1].

1.4.1.4 Preparation of Compound 6

To a solution of compound 5 (0.54 g, 2.1 mmol) in EtOH (8 mL) was addedNaBH₄ (0.12 g, 3.1 mmol) at 0° C., and the mixture was stirred at 25° C.for 2 h. The resulting mixture was quenched with NH₄Cl (Sat.) andextracted with EA (80 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (0.22 g, 41%).LCMS: 268.0 [M+1].

1.4.1.5 Preparation of Compound A07

To a solution of Compound 6 (0.22 g, 0.8 mmol) in MeOH (25 mL) was addedPd(OH)₂/C (45 mg). The mixture was hydrogenated at 25° C. for 16 h under25 Psi pressure. The catalyst was filtered and the filtrate wasconcentrated in vacuo to give the crude product, which was used in thenext step directly (0.1 g, 91%).

1.4.1.6 Preparation of Compound 5′

A mixture of compound 4′ (0.89 g, 2.6 mmol) and KOH (0.22 g, 3.9 mmol)in MeOH/H₂O (10 mL/2 mL) was heated to 55° C. for 2 h. The mixture wasdiluted with EA (80 mL) and washed with brine (60 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to give the crudeproduct, which was used in the next step directly (0.65 g, crude). LCMS:266.0 [M+1].

1.4.1.7 Preparation of Compound 6′

To a solution of compound 5′ (0.65 g, 2.6 mmol) in EtOH (10 mL) wasadded NaBH₄ (0.15 g, 3.9 mmol) at 0° C., and the mixture was stirred at25° C. for 2 h. The resulting mixture was quenched with NH₄Cl (sat.) andextracted with EA (80 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (0.33 g, 50%).LCMS: 268.0 [M+1].

1.4.1.8 Preparation of Compound A08

To a solution of Compound 6′(0.33 g, 1.2 mmol) in MeOH (30 mL) was addedPd(OH)₂/C (60 mg). The mixture was hydrogenated at 25° C. for 16 h under25 Psi pressure. The catalyst was filtered and the filtrate wasconcentrated in vacuo to give the crude product, which was used in thenext step directly (0.15 g, 91%).

Synthesis of the Diastereomers:

1.4.2.1 Preparation of Compound 3

To a solution of Compound 1 (5.0 g, 33.7 mmol) was addedprop-2-en-1-amine (6.0 g, 101.3 mmol), then the solution was stirred at80° C. for 16 h. The mixture was concentrated in vacuum to give crudeCompound 3 (6.6 g) for the next step directly.

1.4.2.2 Preparation of Compound 4

To a solution of Compound 3 (6.6 g, 52.71 mmol) in DCM (80 mL) was addedTEA (10.67 g, 105.4 mmol) and CbzCl (13.49 g, 79.1 mmol) at 0° C., thesolution was stirred at 25° C. for 2 h. The reaction was washed by water(100 mL) and extracted with DCM (100 mL), the organic layer was driedover Na₂SO₄ and concentrated in vacuum to give the crude product, whichwas purified by column chromatography on silica gel (PE:EA=10:1) to giveCompound 4 (5.0 g, 36.6%).

¹H NMR (400 MHz, MeOD): δ ppm: 7.25-7.47 (m, 5H), 5.67-5.96 (m, 2H),5.08-5.23 (m, 3H), 4.91-5.08 (m, 2H), 3.86-3.96 (m, 2H), 3.27 (t, J=7.5Hz, 2H), 1.95-2.11 (m, 2H), 1.53-1.72 (m, 2H).

1.4.2.3 Preparation of Compound 5

To a solution of Compound 4 (3.0 g, 11.57 mmol) in DCM (300 mL) wasadded Grubb's catalyst 1st (290 mg, 0.35 mmol), then the solution wasstirred at 55° C. for 16 h under N₂ atmosphere. The mixture wasconcentrated in vacuum to give the crude product, which was purified bycolumn chromatography on silica gel (PE:EA=20:1) to give Compound 5 (1.9g, 71%) as darkness liquid.

¹H NMR (400 MHz, CDCl₃): δ ppm: 7.30-7.43 (m, 5H), 5.69-5.89 (m, 2H),5.09-5.24 (m, 2H), 3.90-4.08 (m, 2H), 3.47-3.72 (m, 3H), 2.16-2.43 (m,3H), 1.76-1.94 (m, 2H).

1.4.2.41 Preparation of Compound 6

To a solution of Compound 5 (1.0 g, 4.3 mmol) in DCM (15 mL) was addedm-CPBA (1.49 g, 8.65 mmol), then the solution was stirred at 23° C. for16 h. TLC showed the starting materials were consumed completely. Thesolution was washed with aq. Na₂SO₃ and extracted with DCM (20 mL), theorganic layer was dried over Na₂SO₄ and concentrated in vacuum to givethe crude product, which was purified by column chromatography on silicagel (PE:EA=3:1) to give Compound 6 (420 mg, 40%) as colorless liquid.

1.4.2.4 Preparation of Compound 7A and 7B

The compound 6 (800.00 mg, 3.24 mmol) was dissolved in HF/Et3N (522.32mg, 6.48 mmol) a 50 mL single-necked round bottom flask. The mixture wasstirred at 100° C. for 14 h under N₂. After cooled to 20° C., LCMSshowed the starting material was consumed. The residue was washed by aq.NaHCO₃ (80 mL), and extracted by EA (70 mL*2), the organic layers weredried, contracted in vacuum to get the crude product. The crude mixturewas further purification by column chromatography (PE/EA=4:1) to givecompound 7A (320.00 mg, 37.04%) and 7B (70 mg, 8%) as yellow oil.

7A ¹H NMR (400 MHz, CDCl₃): δ ppm: 7.30-7.45 (m, 5H), 5.11-5.27 (m, 2H),4.28-4.64 (m, 1H), 3.21-4.05 (m, 5H), 1.60-2.20 (m, 4H).

7B ¹H NMR (400 MHz, CDCl₃): δ ppm: 7.30-7.48 (m, 5H), 5.12-5.28 (m, 2H),4.21-4.55 (m, 1H), 3.17-4.16 (m, 5H), 1.41-2.12 (m, 4H)

1.4.2.5 Preparation of Compound A07_Trans

To a solution of Compound 7A (460 mg, 1.72 mmol) in CH₃OH (40 mL) wasadded Pd(OH)₂/C (85 mg). The formed mixture was hydrogenated 2.5 h underH₂ atmosphere. The catalyst was filtered and the filtrate wasconcentrated to give the desired product A07_Trans (220 mg, 96%).A08_Trans was prepared from 7B through the same procedure.

1.4.2.6 Preparation of Compound 8

To a mixture of PPh₃ (471.00 mg, 1.80 mmol) in THF (2 mL) and DEAD(312.73 mg, 1.80 mmol) at 0° C., was added the 4-nitrobenzoic acid(300.10 mg, 1.80 mmol,) in THF (15 mL) dropwise, followed by a solutionof compound 7A (400.00 mg, 1.50 mmol) in THF (2 mL). The reactionmixture was stirred at 25° C. for 12 h. TLC showed the starting materialwas consumed. Water (50 mL) was added. The reaction mixture wasextracted by EA (35 ml*3). The organic layers were dried, concentratedin vacuo. The residue was purified by column chromatography (PE/EA=6/1,4/1) to get the desired product compound 8 (200.00 mg, 32.10%). LCMS[M+1]: 417

1.4.2.7 Preparation of Compound 9

To a mixture of compound 8 (150.00 mg, 0.36 mmol) in MeOH (10 mL) wasadded K₂CO₃ (74.68 mg, 0.54 mmol). The mixture was stirred at 25° C. for1.5 hr. TLC showed the reaction was completed. The mixture was purifieddirectly by silica gel chromatography (PE/EA=6/1, 4/1) to affordcompound 9 (70.00 mg, 72.70%) as yellow oil.

1.4.2.8 Preparation of Compound A07_Cis

To a solution of Compound 9 (70 mg, 0.26 mmol) in CH₃OH (20 mL) wasadded Pd(OH)₂ (20 mg). The formed mixture was hydrogenated 2 h under H₂atmosphere. The catalyst was filtered and the filtrate was concentratedto give the desired product C (34 mg, 97%). A08_Cis was prepared from 7Bthrough the same procedure.

1.5 Preparation of A09

1.5.1.1 Preparation of Compound 3

To a solution of Compound 1 (8.0 g, 34.3 mmol) and ethyl 2-diazoacetate(5.1 g, 44.7 mmol) in THF (160 mL) was added BF₃-Et₂O (4.3 mL, 34.3mmol) at −78° C. under N₂. The reaction mixture was stirred at −78° C.for 1.5 h and then warmed to 28° C. slowly, and continued to stir for1.5 h. The resulting mixture was quenched with NaHCO₃ and extracted withEA (500 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to give the crude product, which was purified by flash columnchromatography to give the desired product (7.3 g, 67%). LCMS: 320.0[M+1].

1.5.1.2 Preparation of Compound 4

To a suspension of NaH (464 mg, 11.6 mmol) in THF (40 mL) was added asolution of Compound 3 (3.7 g, 11.6 mmol) in THF (40 mL) at 0° C. underN₂, followed by a solution of Select F (4.4 g, 11.6 mmol) in DMF (20 mL)after 0.5 h. The reaction mixture was stirred at r.t. for 3 h. Theresulting mixture was quenched with NH₄Cl (Sat.) and extracted with EA(300 mL). The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (2.5 g, 64%).LCMS: 338.0 [M+1].

1.5.1.3 Preparation of Compound 5

A mixture of compound 4 (2.5 g, 7.4 mmol) and KOH (0.62 g, 11.1 mmol) inMeOH/H₂O (20 mL/4 mL) was heated to 55° C. for 2 h. The mixture wasdiluted with EA (100 mL) and washed with brine (80 mL). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to give the crudeproduct, which was used in the next step directly (1.8 g, crude). LCMS:266.0 [M+1].

1.5.1.4 Preparation of Compound 6

To a solution of compound 5 (1.8 g, 6.8 mmol) in EtOH (30 mL) was addedNaBH₄ (0.39 g, 10.3 mmol) at 0° C., and the mixture was stirred at 25°C. for 2 h. The resulting mixture was quenched with NH₄Cl (sat.) andextracted with EA (150 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (1.2 g, 66%).LCMS: 268.0 [M+1].

1.5.1.5 Preparation of Compound A09

To a solution of Compound 6 (1.2 g, 4.5 mmol) in MeOH (50 mL) was addedPd(OH)₂/C (0.24 g). The mixture was hydrogenated at 25° C. for 16 hunder 25 Psi pressure. The catalyst was filtered and the filtrate wasconcentrated in vacuo to give the crude product, which was used in thenext step directly (0.59 g, 98%).

Synthesis of the Diastereomers:

5.1.2.1 Preparation of Compound 2

To a mixture of benzyl compound 1 (5.00 g, 21.62 mmol) in CH₂Cl₂ (100mL) was added m-CPBA (9.33 g, 54.05 mmol) in one portion. The mixturewas stirred at 25° C. for 1 h. The mixture was concentrated and theresidue was purified by silica gel chromatography to afford compound 2(2.70 g, 10.92 mmol, 50.50% yield) as yellow soil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=7.41-7.30 (m, 5H), 5.18-5.07 (m, 2H), 4.00-3.79 (m, 2H),3.20 (t, J=4.5 Hz, 2H), 2.91-2.71 (m, 2H), 2.34-2.18 (m, 3H), 2.15-2.03(m, 1H).

5.1.2.2 Preparation of Compound 3

Compound 2 (2.20 g, 8.90 mmol, 1.00 Eq) and HF-Et₃N (2.15 g, 13.35 mmol)were charged in a 100 mL single-necked round bottom flask. The mixturewas stirred at 100° C. for 16 h under N₂. TLC showed the reaction wascomplete. Then it was diluted with DCM (100 mL), washed with brine (100mL×2), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified with column chromatography on silica gel (PE:EA=1:1) to givecompound 3 (1.5 g, 5.61 mmol) as colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=7.42-7.28 (m, 5H), 5.14 (s, 2H), 4.51-4.29 (m, 1H),3.90-3.58 (m, 3H), 3.48-3.25 (m, 2H), 2.29-2.07 (m, 2H), 1.99-1.84 (m,1H), 1.72 (dt, J=5.0, 10.2 Hz, 1H)

5.1.2.3 Preparation of A09_Trans

To a solution of compound 3 (100.0 mg, 374.11 umol, 1.00 Eq) in MeOH (5mL) was added Pd (OH)₂ (0.02 g) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (50 psi) at 25° C. for 16 hours. The reaction mixture wasfiltered and the filter was concentrated to give A09_Trans (40.00 mg,300.39 umol, 80.29% yield) as yellow solid.

5.1.2.4 Preparation of Compound 5

To a solution of compound 3 (400 mg, 1.5 mmol), compound 4 (0.3 g, 1.8mmol) and PPh3 (0.47 g, 1.8 mmol) in THF (10 mL) was added DEAD (0.312g, 1.8 mmol) in dry THF (10 mL) at 0° C. The reaction mixture wasstirred for 16 h at 25° C. TLC showed reaction completed. The mixturewas evaporated and the residue was purified with column chromatographyon silica gel (PE:EA=10:1) to give compound 4 (0.5 g, 80%) as whitesolid.

5.1.2.5 Preparation of Compound 6

To a solution of compound 5 (500 mg, 1.2 mmol) in MeOH (10 mL) was addedK₂CO₃ (165 mg, 1.2 mmol). The reaction mixture was stirred for 1 h at25° C. TLC showed it was complete. The mixture was concentrated to givecompound 6 (300 mg, crude) as yellow oil.

5.1.2.6 Preparation of A09_CIS

To a solution of compound 6 (100.00 mg, 374.11 umol, 1.00 Eq) in MeOH (5mL) was added Pd/C (0.02 g) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (50 psi) at 25° C. for 16 hours. TLC (PE:EtOAc=1:1) showed thestarting material was consumed completely. The reaction mixture wasfiltered and the filter was concentrated to give A09_CIS (40.00 mg,300.39 umol, 80.29% yield) as colorless oil.

1.6 Preparation of A10

1.6.1 Preparation of Compound 3

To a stirred solution of compound 1 (12.37 g, 56.5 mmol) and compound 2(13.56 g, 56.5 mmol) in toluene (800 mL) was added Et₃N (17.17 g, 170mmol). The mixture was heated to 120° C. and stirred for 48 h. TLCshowed starting material was consumed completely. The mixture was washedby saturated NH₄Cl (100 mL) and concentrated in vacuo. The residue waspurified by silica gel chromatography (PE:EA=2:1) to give compound 3 asyellow solid (6.9 g, yield: 41.2%). ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.21(m, 10H), 3.87-3.61 (m, 5H), 2.97-2.41 (m, 8H).

LCMS: 297 [M+1].

1.6.2 Preparation of Compound 4

Compound 3 (2.2 g, 7.5 mmol) was dissolved in MeOH (80 mL), thenPd(OH)₂/C (500 mg) was added. The resulting mixture was hydrogenatedovernight under H₂ atmosphere. TLC showed starting material was consumedcompletely. The catalyst was filtered and the filtrate was concentratedto give the desired compound 4 (0.8 g, 100%) as colorless oil. ¹H NMR(400 MHz, MeOD) δ 3.89-3.71 (m, 1H), 2.97-2.63 (m, 8H).

1.6.3 Preparation of Compound 5

Compound 4 (522 mg, 4.5 mmol) was dissolved in MeOH (30 mL), then Boc₂O(972 mg, 4.5 mmol) and Et₃N (546 mg, 5.4 mmol) was added. The mixturewas stirred at 15° C. for 12 hours. TLC showed starting material wasconsumed completely. The mixture was concentrated in vacuo. The residuewas purification through silica gel column chromatography to give thedesired compound 5 (860 mg, 92%) as colorless oil.

1.6.4 Preparation of Compound 6

To a solution of compound 5 (972 mg, 4.5 mmol) in EtOH (20 mL) wereadded NaBH₃CN (837 mg, 13.5 mmol) and HCHO (1.5 g, 18 mmol) at roomtemperature, then the mixture was stirred at 15° C. for 4 h. TLC showedstarting material was consumed completely. The mixture was concentratedin vacuo. The residue was purified by silica gel column (DCM:MeOH=20:1)to give compound 6 as colorless oil (610 mg, 59%). ¹H NMR (400 MHz,CDCl₃) δ 3.99-3.85 (m, 1H), 3.73-3.27 (m, 4H), 2.97-2.51 (m, 4H),2.46-2.31 (m, 4H), 1.51 (s, 9H).

1.6.5 Preparation of Compound A10

Compound 6 (300 mg, 1.3 mmol) was dissolved in DCM (20 mL), Then TFA (20mL) was added. The resulting mixture was stirred at room temperature for2 hours. TLC showed starting material was consumed completely. Thesolution was concentrated to give crude compound A10 (420 mg, crude) asTFA salt.

1.7 Preparation of A11/12

1.7.1 Preparation of Compound 3

To a solution of Compound 1 (10 g, 80.0 mmol) and NaOH (3.6 g, 90.0mmol) in H₂O (160 mL) was added Compound 2 (5.0 g, 100 mmol) at 0° C.The reaction mixture was heated to 75° C. for 3 h and then cooled to 25°C. (Boc)₂O (21 g, 100 mmol) was added and the mixture was continued tostir for 16 h. The reaction mixture was diluted with water, andextracted with EA (200 mL*2). The organic layer was dried over Na₂SO₄and concentrated in vacuo to give the crude product, which was purifiedby flash column chromatography to give the desired product (11.2 g,57%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.03 (s, 2H), 3.78-3.77 (m, 3H),3.60-3.57 (m, 2H), 2.72-2.67 (m, 2H), 1.51-1.45 (m, 9H).

1.7.2 Preparation of Compound 4

To a solution of Compound 3 (11.2 g, 46 mmol) in EtOH—CHCl₃ (200 mL/10mL) was added PtO2 (1.0 g). The mixture was hydrogenated at 25° C. for16 h under 50 Psi pressure of H2 atmosphere. The catalyst was filteredand the filtrate was concentrated to give the crude product, which wasused in the next step directly (11.3 g, 99%). 1H NMR (400 MHz, CDCl₃): δppm: 8.45-8.43 (m, 2H), 3.91-3.89 (m, 2H), 3.76-3.73 (m, 3H), 3.51-3.48(m, 2H), 3.21-3.19 (m, 2H), 2.10-1.99 (m, 2H), 1.50-1.44 (m, 9H).

1.7.3 Preparation of Compound 5

A solution of compound 4 (2.3 g, 9.3 mmol) in MeOH (20 mL) and NaOH (3N,4 mL) was stirred at 25° C. for 2 h. TLC monitored that the reactioncompleted. The mixture was diluted with EA (150 mL) and washed withbrine (100 mL). The organic layer was dried and concentrated to give thecrude product, which was purified by column chromatography to give thedesired product (1.25 g, 63%). ¹H NMR (400 MHz, CDCl₃): δ ppm: 4.10-4.05(m, 2H), 3.60-3.58 (m, 2H), 3.31-3.28 (m, 2H), 1.91-1.85 (m, 2H),1.63-1.45 (m, 9H).

1.7.4 Preparation of Compound A11

To a solution of compound 5 (0.5 g, 2.3 mmol) in DCM (5 mL) was addedTFA (5 mL), and stirred at 25° C. for 2 h. TLC monitored that thereaction completed. The mixture was concentrated to give the crudeproduct (780 mg, crude).

1.7.5 Preparation of Compound 6

To a solution of compound 4 (800 mg, 3.7 mmol) in THF (20 mL) was addedNaH (224 mg, 5.6 mmol), and stirred at 25° C. for 0.5 h. Then, MeI (795mg, 5.6 mmol) was added. The mixture was stirred at room temperatureuntil TLC monitored that the reaction completed. The mixture wasquenched with water, diluted with EA (50 mL) and washed with brine (30mL). The organic layer was dried and concentrated to give the crudeproduct, which was purified by column chromatography to give the desiredproduct (720 mg, 63%).

1.7.6 Preparation of Compound A12

To a solution of compound 6 (720 mg, 2.3 mmol) in DCM (5 mL) was addedTFA (5 mL), and stirred at 25° C. for 2 h. TLC monitored that thereaction completed. The mixture was concentrated to give the crudeproduct (960 mg, crude).

1.8 Preparation of A13

1.8.1 Preparation of Compound 3

To a solution of Compound 1 (1.32 g, 10.5 mmol) in DMF (20 mL) was addedNaH (960 mg, 24 mmol) at 0° C., the mixture was stirred at 0° C. for 30min. Then compound 2 (1.61 g, 10 mmol) was added at 0° C. The mixturewas stirred at 15° C. for 2 hours. TLC showed that starting material wasconsumed completely. Saturated NH₄Cl (100 mL) was added to quench thereaction. The solvent was removed in vacuo and the residue was extractedwith EA (100 mL*2). The organic layer was concentrated and purified bysilica gel column (PE:EA=4:1) to give compound 3 (1.1 g, yield: 51%) ascolorless oil. ¹H NMR (400 MHz, CDCl₃): δ: 5.12-4.91 (m, 2H), 4.29-4.03(m, 4H), 3.76-3.45 (m, 4H), 1.47 (s, 9H).

1.8.2 Preparation of Compound 4

To a solution of compound 3 (212 mg, 1 mmol) in THF/H₂O (3 mL/3 mL) wereadded K₂OsO₄.2H₂O (18 mg, 0.05 mmol) and NaIO₄ (491 mg, 2.3 mmol) atroom temperature, then the mixture was stirred at 15° C. for 4 h. TLCshowed starting material was consumed completely. The mixture wasconcentrated in vacuo. The residue was purified by silica gel column(PE:EA=5:1) to give compound 4 as yellow oil (170 mg, 77%). LCMS: 216[M+1].

1.8.3 Preparation of Compound 5

To a solution of compound 4 (425 mg, 2 mmol) in EtOH (10 mL) was addedNaBH₄ (150 mg, 4 mmol). The mixture was stirred at 15° C. for 4 h. TLCshowed starting material was consumed. Saturated NH₄Cl (20 mL) was addedto quench the reaction. The mixture was concentrated in vacuo. Theresidue was extracted with EA (50 mL), dried over Na₂SO₄ andconcentrated in vacuo to give the desired compound 5 (370 mg, 87%) ascolorless oil.

1.8.4 Preparation of Compound A13

Compound 5 (420 mg, 2 mmol) was dissolved in DCM (20 mL), Then TFA (20mL) was added. The resulting mixture was stirred at room temperature for2 hours. TLC showed starting material was consumed completely. Thesolution was concentrated to give desired crude compound 5 (620 mg,100%) as TFA salt, used in next step directly.

1.9 Preparation of A15

1.9.1 Preparation of Compound 3

A mixture of Compound 1 (8.7 g, 65.7 mmol), Compound 2 (3.5 g, 32.7mmol) and K₂CO₃ (9.06 g, 65.7 mmol) in DMF (120 mL) was heated to 100°C. for 16 h. The mixture was diluted with EA (100 mL), and washed withH₂O (100 mL*3). The organic phase was dried over Na₂SO₄ and concentratedin vacuo to give the crude product, which was purified by columnchromatography to give the desired product 3 as colorless oil (5.1 g,72.5%). LCMS: 256 [M+1].

1.9.2 Preparation of Compound 4

To a solution of Compound 3 (1.5 g, 6.97 mmol) in toluene (15 mL) wasadded CbzCl (1.42 g, 8.37 mmol). The mixture was heated to 110° C. for16 h. The mixture was concentrated in vacuo. The residue was dissolvedwith water and EA. The organic layer was washed with aq. Na₂CO₃, driedover Na₂SO₄ and concentrated in vacuo to give the crude product, whichwas purified by column chromatography to give the desired product 4 ascolorless oil (1.24 g, Yield: 68.9%). LCMS: 260 [M+1].

1.9.3 Preparation of Compound 5

To a solution of Compound 4 (1.0 g, 3.86 mmol) in DCM (60 mL) was addedDichloride Zhan catalyst 1B (150 mg, CAS: 918870-76-5). The mixture waspurged with N₂ for 10 min and stirred at 20° C. for 16 h. The mixturewas concentrated in vacuo to give the crude product, which was purifiedby column chromatography to give the desired product 5 as colorless oil(800 mg, Yield: 89.7%). LCMS: 232 [M+1].

1.9.4 Preparation of Compound 6

To a solution of compound 5 (800 mg, 3.46 mmol) in DCM (30 mL), wasadded m-CPBA (774 mg, 4.5 mmol). The mixture stirred at room temperaturefor 5 hours. The solution was quenched by aq. Na₂SO₃, and extracted withDCM (60 mL*2). The organic combined phase was dried over Na₂SO₄, andconcentrated to give desired compound 7 as colorless oil (812 mg, Yield:95.9%). LCMS: 248 [M+1].

1.9.5 Preparation of Compound 7

Compound 6 (812 mg, 3.31 mmol) was dissolved in MeOH (10 mL), thenconcentrated H₂SO₄ (200 mg) was added. The mixture stirred at roomtemperature for 1 h. The solution was neutralized with aq.Na₂CO₃ topH=7. The resulting mixture was concentrated in vacuo. The residue wasextracted with EA (60 mL*2). The combined organic phase was dried overNa₂SO₄, and concentrated in vacuo to give the crude product, which waspurified by column chromatography to give the desired product 8 ascolorless oil (778 mg, Yield: 84.9%). LCMS: 280 [M+1].

1.9.6 Preparation of Compound A15

To a solution of Compound 7 (778 mg, 2.8 mmol) in MeOH (70 mL) was addedPd(OH)₂/C (100 mg) under N₂. The mixture was stirred under H₂ balloon at23° C. for 2 h. The mixture was filtrated. The filtrates wasconcentrated to give the desired product 8 (310 mg, Yield: 78%).

1.10 Preparation of A16/17/18

1.10.1 Preparation of Compound 3

A mixture of Compound 1 (5.0 g, 33.7 mmol) and Compound 2 (6.0 g, 101.3mmol) was heat to 80° C. for 16 h. The mixture was concentrated invacuo. The residue was dissolved with DCM (100 mL). Et₃N (7.6 g, 75.6mmol) followed by CbzCl (12.8 g, 75.6 mmol) at 0° C. The reactionmixture was stirred at rt for 16 h. The mixture was diluted with DCM(100 mL) and washed with water (100 mL). The organic layer was driedover Na₂SO₄ and concentrated in vacuo to give the crude product whichwas purified by column chromatography on silica gel (PE:EA=10:1) to giveCompound 4 (4.4 g, 34%). LCMS: 260 [M+1]. ¹H NMR (400 MHz, MeOD) δ7.49-7.22 (m, 5H), 5.95-5.67 (m, 2H), 5.13 (s, 4H), 5.08-4.91 (m, 2H),3.91 (d, J=5.6 Hz, 2H), 3.31-3.23 (m, 2H), 2.02 (s, 2H), 1.74-1.57 (m,2H).

1.10.3 Preparation of Compound 4

To a solution of Compound 3 (2.0 g, 7.7 mmol) in DCM (100 mL) was addedDichloride Zhan catalyst 1B (236 mg, CAS: 918870-76-5). The reactionmixture was stirred at rt for 16 h under N₂ atmosphere. The mixture wasconcentrated in vacuo to give the crude product which was purified bycolumn chromatography on silica gel (PE:EA=10:1) to give Compound 4(1.28 g, 72%) as darkness liquid. LCMS: 232 [M+1]. ¹H NMR (400 MHz,MeOD) δ 7.40-7.27 (m, 5H), 5.95-5.62 (m, 2H), 5.13 (d, J=3.5 Hz, 2H),3.99 (d, J=2.8 Hz, 2H), 3.63 (d, J=6.1 Hz, 2H), 2.28-2.19 (m, 3H),1.89-1.75 (m, 2H).

1.10.4 Preparation of Compound 5

To a solution of Compound 5 (900 mg, 3.9 mmol) in DCM (40 mL) was addedm-CPBA (1.34 g, 7.8 mmol), and stirred at rt for 16 h. TLC showedmaterials was consumed completed. The reaction mixture was quenched withNa₂SO₃ solution and extracted with DCM (20 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the crude productwhich was purified by column chromatography on silica gel (PE:EA=30:1)to give Compound 6 (900 mg, 83%) as colorless liquid. LCMS: 248 [M+1].¹H NMR (400 MHz, MeOD) δ 7.37 (s, 6H), 5.19-5.08 (m, 2H), 4.32-4.18 (m,1H), 3.86-3.74 (m, 1H), 3.56-3.38 (m, 1H), 3.19-3.08 (m, 2H), 2.80-2.66(m, 1H), 2.31-2.17 (m, 1H), 2.02-1.94 (m, 1H), 1.79-1.51 (m, 2H).

1.10.5 Preparation of Compound 6 and 6′

To a solution of Compound 6 (700 mg, 2.83 mmol) in MeOH (40 mL) wasadded concentrated H₂SO₄ (0.1 mL) at rt and the solution was stirred for1 h. TLC showed materials was consumed completed. An aqueous solution ofNaHCO₃ (1 mL) was added to neutralize the reaction mixture. Theresulting mixture was concentrated in vacuo, then EtOAc (40 mL) andwater (20 mL) was added to dissolve the residue. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the crude productwhich was purified by column chromatography on silica gel (PE:EA=10:1)to give a mixture of Compound 7B and 7C (700 mg, yield 88.6%) ascolorless liquid.

1.10.6 Preparation of Compound A16 and A11

To a solution of a mixture of Compound 7B and 7C (800 mg, 2.86 mmol) inMeOH (20 mL) was added Pd(OH)₂/C (200 mg) and the mixture was stirredfor 4 h under H₂ balloon. TLC showed materials was consumed completedthe solution was filtered and the filtrate concentrated in vacuum togive a mixture of Compound C and D (370 mg, yield 88%) as liquid.

1.10.7 Preparation of Compound 7

To a solution of Compound 4 (260 mg, 1.12 mmol) in THF (5 mL) and water(2 mL) was added OsO₄ (60 mg), followed by NMO (131 mg). The reactionwas stirred at rt for 3 h. TLC showed materials was consumed completed.The mixture was diluted with water and extracted with EtOAc (30 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to givethe crude product Compound 8 (186 mg, 62%) as colorless liquid. LCMS:266 [M+1]. ¹H NMR (400 MHz, MeOD) δ 7.43-7.29 (m, 5H), 5.21-5.07 (m,2H), 3.88-3.81 (m, 1H), 3.81-3.65 (m, 3H), 3.32-3.17 (m, 2H), 2.02-1.87(m, 2H), 1.74-1.45 (m, 2H).

1.10.8 Preparation of Compound A18

To a solution of Compound 7 (186 mg, 0.77 mmol) in MeOH (20 mL) wasadded Pd(OH)₂/C (40 mg) at rt and was stirred for 4 h under H₂ balloon.The mixture was filtered and the filtrate concentrated in vacuo to givethe crude product Compound E (101 mg, 100%) as liquid.

1.11 Preparation of A22

1.11.1 Preparation of Compound 2

To a solution of Compound 1 (0.5 g, 2.0 mmol) in THF (30 mL) was addedLiHMDS (4.0 mL, 4.0 mmol) at −78° C. under N₂. The reaction mixture wasstirred at −78° C. for 2 h. MeI (0.86 g, 6.0 mmol) was added to themixture at −78° C., then warmed to 28° C. slowly and stirred for 1.5 h.

The resulting mixture was quenched with H₂O and extracted with EA (50mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto give a crude product, which was purified by flash columnchromatography to give Compound 2 (0.4 g, 75%). 1H NMR (400 MHz,CHLOROFORM-d) δ 7.29-7.41 (m, 1H), 5.03-5.23 (m, 1H), 3.84-4.22 (m, 1H),2.60-3.23 (m, 2H), 2.46-2.59 (m, 1H), 1.69-1.90 (m, 2H), 1.09 (dd,J=6.84, 15.12 Hz, 3H), LCMS: 262.0 [M+1].

1.11.3 Preparation of Compound 3

To a solution of compound 2 (1.2 g, 4.6 mmol) in EtOH (20 mL) was addedNaBH₄ (259 mg, 6.8 mmol) at 0° C., and the mixture was stirred at 25° C.for 2 h. The resulting mixture was quenched with NH₄Cl (sat.) andextracted with EA (80 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purified byflash column chromatography to give the desired product (650 mg, 54%).LCMS: 264.0 [M+1].

1.11.4 Preparation of Compound A22

To a solution of Compound 3 (0.26 g, 1.0 mmol) in MeOH (25 mL) was addedPd(OH)₂ (50 mg). The mixture was hydrogenated at 25° C. for 16 h under25 Psi pressure. The catalyst was filtered and the filtrate wasconcentrated to give the crude product, which was used in the next stepdirectly (0.1 g, 77%).

1.12 Preparation of A23

1.12.1 Preparation of Compound 2

To a solution of Compound 1 (2.0 g, 7.0 mmol) in THF (50 mL) was addedNaH (336 mg, 8.4 mmol) at 0° C. under N₂. The reaction mixture wasstirred at 0° C. for 0.5 h. MeI (1.5 g, 10.5 mmol) was added to themixture at 0° C., then warmed to 28° C. slowly and stirred for 16 h. Theresulting mixture was quenched with H₂O and extracted with EA (50 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo togive a crude product, which was purified by flash column chromatographyto give Compound 2 (1.5 g, 71.4%).

1.12.2 Preparation of Compound 3

A mixture of compound 2 (1.5 g, 5 mmol) and KOH (0.5 g, 9.0 mmol) inMeOH/H₂O (20 mL/4 mL) was heated to 55° C. for 2 h. The mixture wasdiluted with EA (80 mL) and washed with brine (60 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to give a crude product,which was used in the next step directly (1.5 g, 94%).

1.12.3 Preparation of Compound 4

To a solution of compound 3 (1.3 g, 5.7 mmol) in EtOH (20 mL) was addedNaBH₄ (260 mg, 6.9 mmol) at 0° C., and the mixture was stirred at 25° C.for 2 h. The formed mixture was quenched with NH₄Cl (Sat.) and extractedwith EA (80 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a crude product, which was purified byflash column chromatography to give the desired product (821 mg, 63%).

1.12.4 Preparation of Compound A23

To a solution of Compound 4 (0.82 g, 3.6 mmol) in MeOH (10 mL) was addedHCl/MeOH (4 mL, 4 M). The mixture was stirred at 25° C. for 2 h. Themixture was concentrated to give the crude HCl salt, which was used inthe next step directly (760 mg, crude HCl salt).

1.13 Preparation of A24

1.13.1 Preparation of Compound 2

To a solution of Compound 1 (1 g, 6.4 mmol) in THF (30 mL) was addedLiHMDS (12.8 mL, 12.8 mmol) at −78° C. under N₂. The reaction mixturewas stirred at −78° C. for 2 h. MeI (2.7 g, 19.2 mmol) was added to themixture at −78° C., then warmed to 28° C. slowly and stirred for 15 h.The resulting mixture was quenched with H₂O and extracted with EA (50mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto give a crude product, which was purified by flash columnchromatography to give Compound 2 (0.62 g, 57%). ¹H NMR (400 MHz,CHLOROFORM-d) δ 3.92-4.17 (m, 4H), 2.55-2.83 (m, 2H), 2.31-2.43 (m, 1H),1.87-2.13 (m, 3H), 1.69-1.81 (m, 1H), 1.04 (d, J=6.65 Hz, 3H). LCMS:171.0 [M+1].

1.13.2 Preparation of Compound 3

To a solution of Compound 2 (0.5 g, 2.9 mmol) in EtOH/H₂O (20/1 mL) wasadded NH₂OH.HCl (1.0 g, 14.7 mmol) and NaOAc (0.7 g, 8.8 mmol). Themixture was stirred at 25° C. for 16 h. The resulting mixture wasdiluted with EA (80 mL) and washed with brine (60 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo to give a crude product,which was purified by flash column chromatography to give Compound 3(0.4 g, 73%). LCMS: 186.0 [M+1].

1.13.3 Preparation of Compound 4

To a solution of Compound 3 (1.0 g, 5.4 mmol) in Acetone (20 mL) wasadded TosCl (1.5 g, 8.1 mmol). NaOAc (1.7 g, 16.2 mmol) in H₂O (30 mL)was added to the mixture. The mixture was stirred at 16° C. for 2 h,then warmed to 40° C. slowly and stirred for 16 h. The resulting mixturewas diluted with DCM (200 mL) and washed with brine (60 mL). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to give a crudeproduct, which was purified by flash column chromatography to giveCompound 4 (0.9 g, 83%).

1.13.4 Preparation of Compound 5

To a solution of Compound 4 (0.9 g, 4.8 mmol) in THF (15 mL) was addedLiAlH₄ (0.27 g, 7.2 mmol) at 16° C. The mixture was stirred at 16° C.for 5 h. The mixture was quenched with water and filtered, then CbzCl(1.2 g, 7.2 mmol) was added to the solution. The mixture was stirred at40° C. for 12 h. The resulting mixture was diluted with EA (20 mL) andwashed with brine (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a crude product, which was purified byflash column chromatography to give Compound 5 (0.75 g, 60%).

1.13.4 Preparation of Compound 5

To a solution of Compound 4 (0.9 g, 4.8 mmol) in THF (15 mL) was addedLiAlH₄ (0.27 g, 7.2 mmol) at 16° C. The mixture was stirred at 16° C.for 5 h. The mixture was quenched with water and filtered. t CbzCl (1.2g, 7.2 mmol) was added to the filtrate. The mixture was stirred at 40°C. for 12 h. The resulting mixture was diluted with EA (20 mL) andwashed with brine (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a crude product, which was purified byflash column chromatography to give Compound 5 (0.75 g, 60%).

1.13.5 Preparation of Compound 6

To a solution of Compound 5 (0.75 g, 2.3 mmol) in acetone (15 mL) andwater (5 mL) was added TosOH (0.6 g, 3.4 mmol) at 16° C. The mixture wasstirred at 40° C. for 12 h. The resulting mixture was diluted with EA(20 mL) and washed with brine (20 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo to give a crude product, which waspurified by flash column chromatography to give Compound 6 (0.3 g, 50%).

1.13.6 Preparation of Compound 7

To a solution of Compound 6 (0.30 g, 1.1 mmol) in THF (15 mL), was addedNaBH₄ (50 mg, 1.3 mmol) at 16° C. The mixture was stirred at 16° C. for3 h. The resulting mixture was diluted with EA (20 mL) and washed withbrine (20 mL). The organic layer was dried over Na₂SO₄ and concentratedin vacuo to give Compound 7 (0.30 g, 98%).

1.13.8 Preparation of Compound A24

To a solution of Compound 7 (0.30 g, 1.1 mmol) in MeOH (25 mL) was addedPd/C (50 mg). The mixture was hydrogenated at 25° C. for 16 h under H₂atmosphere. The catalyst was filtered and the filtrate was concentratedto give the crude product, which was used in the next step directly(0.14 g, 98%).

1.14 Preparation of A25

1.14.1 Preparation of Compound 3

To a mixture of Indium (19.75 g, 172.03 mmol, 1.30 Eq) and3-bromoprop-1-ene (20.81 g, 172.03 mmol, 1.30 Eq) in H₂O (400 mL), wasadded 2-chloroacetaldehyde (25.97 g, 132.33 mmol, 1.00 Eq) in oneportion at 25° C. under N₂. The mixture was stirred at 25° C. for 16 hr.Then the mixture was filtered, the filtrate was extracted with EtOAc,the combined organic layer was dried over anhydrous Na₂SO₄, concentratedto afford 1-chloropent-4-en-2-ol (13.00 g, 107.81 mmol, 81.47% yield) asyellow oil. ¹H NMR (400 MHz, CDCl3) δ5.79-5.89 (m, 1H), 5.13-5.25 (m,2H), 3.86-3.97 (m, 1H), 3.62-3.70 (m, 1H), 3.50-3.59 (m, 1H), 2.32-2.46(m, 2H), 2.24 (brs, 1H).

1.14.2 Preparation of Compound 5

A mixture of 1-chloropent-4-en-2-ol (23.40 g, 194.06 mmol, 1.00 Eq) andprop-2-en-1-amine (33.00 g, 578.03 mmol, 2.98 Eq) was stirred at 90° C.for 16 hr. The mixture was cooled to 25° C. and concentrated in reducedpressure at 60° C. The residue was poured into ice-water (w/w=1/1) (150mL) and stirred for 20 min. The aqueous phase was extracted with EA. Thecombined organic phase was washed with saturated brine (200 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by silica gel chromatography (DCM:MeOH=30/1 to 10/1) toafford 1-(allylamino)pent-4-en-2-ol (16.00 g, 113.31 mmol, 58.39% yield)as yellow oil.

1.14.3 Preparation of Compound 6

To a solution of 1-(allylamino)pent-4-en-2-ol (4.23 g, 29.96 mmol, 1.00Eq) in DCM (50 mL) was added CbzCl (6.13 g, 35.95 mmol, 1.20 Eq) and TEA(6.06 g, 59.92 mmol, 2.00 Eq). The mixture was stirred at 25° C. for 4hr. TLC detected the material was consumed completely, the mixture waswashed with water, the aqueous layer was extracted with DCM, thecombined organic layer was dried over anhydrous Na₂SO₄, concentrated andpurified by silica gel chromatography (eluting with PE:EA=10:1) toafford desired product benzyl N-allyl-N-(2-hydroxypent-4-enyl) carbamate(6.10 g, 22.15 mmol, 73.95% yield) as yellow oil. LCMS: 276.0 [M+1].

1.14.4 Preparation of Compound 7

To a solution of benzyl N-allyl-N-(2-hydroxypent-4-enyl)carbamate (6.10g, 22.15 mmol, 1.00 Eq) in DCM (400 mL) was added Zhan catalyst 1B(812.63 mg, 1.11 mmol, 0.05 Eq) under N₂ protection. The mixture wasstirred at 25° C. for 16 hr under N₂ protection. Then TLC detected thereaction was completed, the solvent was evaporated, the residue waspurified by chromatography (silica gel, eluting with PE:EA=2:1) toafford benzyl 3-hydroxy-2,3,4,7-tetrahydroazepine-1-carboxylate (2.60 g,10.51 mmol, 47.47% yield) as yellow oil. ¹H NMR (400 MHz, CDCl3) δ7.30-7.46 (m, 5H), 5.63-5.89 (m, 2H), 5.19 (s, 2H), 3.96-4.13 (m, 2H),3.74-3.90 (m, 2H), 3.54-3.70 (m, 1H), 2.43 (m, 2H).

1.14.5 Preparation of Compound 8

To a solution of benzyl3-hydroxy-2,3,4,7-tetrahydroazepine-1-carboxylate (300.00 mg, 1.21 mmol,1.00 Eq) in DCM (10 mL) was added ZnEt₂ (2 M, 1.21 mL, 2.00 Eq) at 0° C.under N₂ protection. Then the mixture was stirred at 0° C. for 30 mins,and ClCH₂I (533.55 mg, 3.03 mmol, 2.50 Eq) was added. The resultingmixture was stirred at 25° C. for 16 hrs. LCMS detected 75% desiredproduct and 15% material remained. The mixture was poured into NH₄Clsolution, and extracted with EA, the combined organic layer was driedover Na₂SO₄, concentrated, the residue was diluted in THF (3 mL) and H₂O(3 mL), NaIO₄ (258.81 mg, 1.21 mmol, 1.00 Eq) and K₂OsO₄ (230.21 mg,1.21 mmol, 1.00 Eq) was added, the mixture was stirred at 25° C. for 30mins, then the reaction was quenched by saturated Na₂SO₃, extracted withEA, the combined organic layer was dried over Na₂SO₄, concentrated, theresidue was purified by silica gel chromatography (PE:EA=3:1) to affordbenzyl 3-hydroxy-5-azabicyclo[5.1.0]octane-5-carboxylate (110.00 mg,420.94 umol, 34.79% yield) as colorless oil. LCMS: 262.0 [M+1].

1.14.6 Preparation of Compound A25

To a solution of benzyl3-hydroxy-5-azabicyclo[5.1.0]octane-5-carboxylate (110.00 mg, 420.94umol, 1.00 Eq) in MeOH (10 mL) was added Pd—C under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ at 25° C. for 4 hr. TLC showed the startingmaterial was consumed completely. The reaction mixture was filtered andthe filter was concentrated to give 5-azabicyclo[5.1.0]octan-3-ol (37.00mg, 290.93 umol, 69.11% yield) as colorless oil.

1.15 Preparation of A26/A27

1.15.1 Preparation of Compound 2A and 2B

At ice bath, to a solution of compound 1 (9.0 g, 23.2 mmol)) in THF (135mL) was added BH₃-Me₂S (7.0 mL, 70.0 mmol). After the solution stirringat rt overnight, 3 M NaOH (9.3 mL, 27.8 mmol) and H₂O₂ (14.7 g, 116.0mmol) were added in turn at ice bath and stirred at rt for 2 hrs. Themixture was quenched with Na₂SO₃ solution, extracted with EtOAc (200mL*2) and the organic layer was concentrated to give a crude mixedproduct, which was used for the next step directly (9.36 g, 99.6%).

1.15.2 Preparation of Compound 3A and 3B

A mixture of Compound 2A and 2B (9.36 g, 23.0 mmol) and Dess-Martinreagent (11.72 g, 27.6 mmol) in DCM (160 mL) was stirred at rt under N₂overnight. The mixture was quenched with Na₂SO₃ solution, extracted withDCM (150 mL*2) and the organic layer was concentrated to give the crudeproduct, which was purified by Biotage chromatography to give theCompound 3A (4.6 g) and Compound 3B (2.2 g). LCMS: 427 [M+23]

Compound 10A ¹H NMR (400 MHz, CDCl₃, 10A): δ ppm: 8.27-8.30 (m, 2H),7.93-7.96 (m, 2H), 7.36-7.43 (m, 5H), 4.60-4.67 (m, 2H), 4.05 (d, J=18.2Hz, 1H), 3.82-3.87 (m, 1H), 3.75 (d, J=18.2 Hz, 1H), 3.62-3.66 (dd,J=14.6 Hz, 3.0 Hz, 1H), 3.32-3.37 (dd, J=14.6 Hz, 7.0 Hz, 1H), 2.63-2.67(m, 2H), 2.06-2.09 (m, 1H), 1.82-1.86 (m, 1H).

Compound 10B ¹H NMR (400 MHz, CDCl₃, 10B): δ ppm: 8.18-8.21 (m, 2H),7.94-7.97 (m, 2H), 7.27-7.37 (m, 5H), 4.62 (d, J=11.2 Hz, 1H), 4.51 (d,J=11.2 Hz, 1H), 3.75-3.93 (m, 3H), 3.49-3.56 (m, 2H), 3.02-3.08 (m, 1H),2.91-2.95 (m, 1H), 2.56-2.71 (m, 2H).

1.15.3 Preparation of Compound 4A

A solution of Compound 3A (4.6 g, 11.4 mmol) and NaBH₄ (0.43 g, 11.4mmol) in MeOH (40 mL) and THF (20 mL) was stirred at rt for 30 minutes.The mixture was quenched with NH₄Cl solution, evaporated the solvent,extracted with EA (150 mL*2) and the organic layer was concentrated togive the crude product, which was purified by Biotage chromatography togive the desired product as a white solid (4.21 g, 91%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 8.28-8.34 (m, 2H), 7.98-8.00 (m, 2H),7.28-7.38 (m, 5H), 4.48-4.58 (m, 2H), 4.00-4.04 (m, 1H), 3.77-3.84 (m,1.4H), 3.54-3.57 (m, 1.6H), 3.28-3.38 (m, 1H), 3.17-3.23 (m, 0.6H),3.03-3.09 (m, 0.4H), 2.42-2.67 (m, 1H), 1.60-2.14 (m, 4H).

1.15.4 Preparation of Compound 5A

To a solution of Compound 5A (1.8 g, 4.4 mmol) in DCM (20 mL) was addedDAST (1.78 g, 11 mmol) at −60° C. under N₂. The solution was stirred atice bath for 2 hrs. Quenched with NaHCO3 solution, extracted with DCM(100 mL*2) and the organic layer was concentrated to give the crudeproduct, which was purified by Biotage chromatography to give thedesired product as a white solid (480 mg, 26.7%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 8.25 (d, J=8.8 Hz, 2H), 7.99 (d, J=8.8Hz, 2H), 7.31-7.40 (m, 5H), 4.80-4.93 (m, 1H), 4.50-4.57 (m, 2H),3.40-3.75 (m, 5H), 1.78-2.07 (m, 4H).

1.15.5 Preparation of Compound 6A

At ice bath, to a solution of Compound 5A (480 mg, 1.17 mmol) in DMF (8mL) was added LiOH (296 mg, 7.06 mmol), followed by HSCH₂CO₂H (216 mg,2.35 mmol) under N₂. The mixture was stirred at rt for 2 hrs. Boc₂O (279mg, 1.29 mmol) was added and stirred at rt for another 30 minutes. Themixture was quenched with NaClO solution, extracted with EA (50 mL*2)and the organic layer was concentrated to give the crude product, whichwas purified by silica gel chromatography to give the desired product asan oil (300 mg, 79.3%). LCMS: 346 [M+23]

1.15.6 Preparation of Compound 7A

To a solution of Compound 6A (300 mg, 0.9 mmol) in CH₃OH (50 mL) wasadded Pd(OH)₂/C (300 mg). The mixture was hydrogenated at 60° C. under50 Psi of hydrogen pressure overnight. The catalyst was filtered and thefiltrate was concentrated to give the desired product as oil (160 mg,73.7%).

1.15.6 Preparation of Compound 26A

4M HCl-MeOH (10 mL) was added to Compound 13A (160 mg, 0.68 mmol). Thenthe solution was stirred at rt for 10 minutes. The solvent wasevaporated and the residue was basified with Et₃N. It was used for thenext step directly.

1.15.7 Preparation of Compound 4B

A solution of Compound 3B (2.2 g, 5.4 mmol) and NaBH₄ (0.20 g, 5.4 mmol)in MeOH (20 mL) and THF (10 mL) was stirred at rt for 1 hr. The mixturewas quenched with NH₄Cl solution, evaporated the solvent, extracted withEA (50 mL*2) and the organic layer was concentrated to give the crudeproduct, which was purified by Biotage chromatography to give thedesired product as an oil (1.79 g, 81%).

¹H NMR (400 MHz, CDCl₃, 9B): δ ppm: 8.27-8.33 (m, 2H), 7.94-7.97 (m,2H), 7.27-7.35 (m, 5H), 4.52-4.58 (m, 2H), 4.11-4.17 (m, 1H), 3.92-3.95(m, 1H), 3.54-3.72 (m, 2H), 3.17-3.41 (m, 2H), 1.84-2.21 (m, 4H).

1.15.8 Preparation of Compound 5B

To a solution of Compound 4B (2.16 g, 5.3 mmol) in DCM (30 mL) was addedDAST (2.14 g, 13.3 mmol) at −60° C. under N₂. The solution was stirredat rt for 3 hrs. The mixture was quenched with NaHCO₃ solution,extracted with DCM (100 mL*2) and the organic layer was concentrated togive the crude product, which was purified by silica gel chromatographyto give the desired product as a slight yellow solid (1.48 g, 68%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 8.30-8.33 (m, 2H), 7.94-7.99 (m, 2H),7.31-7.40 (m, 5H), 4.75-5.04 (m, 1H), 4.51-4.66 (m, 2H), 3.11-3.96 (m,5H), 2.01-2.27 (m, 4H).

1.15.9 Preparation of Compound 6B

At ice bath, to a solution of Compound 5B (560 mg, 1.37 mmol) in DMF (8mL) was added LiOH (346 mg, 8.23 mmol), followed by 2-mercaptoaceticacid (252 mg, 2.74 mmol) under N₂. The mixture was stirred at rt for 1hr. Boc₂O (444 mg, 2.06 mmol) was added and stirred at rt for another 30minutes. Quenched with NaClO solution, extracted with EA (50 mL*2) andthe organic layer was concentrated to give the crude product, which waspurified by silica gel chromatography to give the desired product as anoil (300 mg, 67.8%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 7.30-7.40 (m, 5H), 4.94-5.05 (m, 1H),4.57-4.65 (m, 2H), 3.59-4.09 (m, 3H), 2.95-3.32 (m, 2H), 1.99-2.40 (m,4H), 1.43-1.49 (m, 9H).

1.15.10 Preparation of Compound 7B

To a solution of Compound 6B (300 mg, 0.9 mmol) in CH₃OH (20 mL) wasadded Pd(OH)₂ (200 mg). The mixture was hydrogenated at 60° C. under 50Psi of hydrogen pressure overnight. The catalyst was filtered and thefiltrate was concentrated to give the desired product as oil (200 mg,91.7%).

1.15.11 Preparation of Compound A27

4M HCl-MeOH (10 mL) was added to Compound 7B (190 mg, 0.81 mmol). Thenthe solution was stirred at rt for 10 minutes. The solvent wasevaporated and the residue was basified with Et₃N. It was used for thenext step directly.

1.16 Preparation of A28

1.16.1 Preparation of Compound 2

To a mixture of 1,3-dichloropropan-2-one (20.00 g, 157.52 mmol, 1.00 Eq)in THF (94 mL), was added PPh₃ (37.18 g, 141.77 mmol, 0.90 Eq) in oneportion at 14° C. The mixture was stirred at 80° C. for 18 hr. Themonophosphonium chloride thus formed was isolated by filtration and thentreated with a solution of Na₂CO₃ (20.03 g, 189.02 mmol, 1.20 Eq)/MeOH(250 mL)-H2O (250 mL) at 14° C. After 18 hr, a precipitate appeared, andwas filtered from the solution to give compound 2 (55.57 g, 82.78%) aswhite solid.

1.16.2 Preparation of Compound 4

To a mixture of tert-butyl N-but-3-enylcarbamate (3.16 g, 18.42 mmol,1.30 Eq) in THF (20 mL), was added n-BuLi (2.5 M, 14.74 mL, 2.60 Eq) at−78° C. under N₂. The mixture was stirred at −20° C. for 1 hr. Then1-chloro-3-(triphenyl phosphoranylidene)propan-2-one (5.00 g, 14.17mmol, 1.00 Eq) in THF (20 mL) was added to the mixture at −78° C. underN₂. The mixture was stirred at −20° C. for 3 hr. The resulting mixturewas poured into water (30 mL) and stirred for 20 min. The aqueous phasewas extracted with EA (10 mL). The combined organic phase was washedwith saturated brine (20 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (PE/EA=1/1) to afford ttert-butylbut-3-en-1-yl(2-oxo-3-(triphenylphosphoranylidene)propyl)carbamate (5.80g, 11.90 mmol, 83.98% yield) as yellow solid.

1.16.3 Preparation of Compound 5

To a mixture of tert-butylN-but-3-enyl-N-[2-oxo-3-(triphenyl-phosphanylidene) propyl]carbamate(5.80 g, 11.90 mmol, 1.00 Eq) in THF (30 mL), was added HCHO (96.58 g,1.19 mol, 100.00 Eq) in one portion at 18° C. The mixture was stirred at18° C. for 15 hr. TLC showed the reaction was completed. The mixture wasextracted with PE (100 mL*3). The combined organic phase was washed withsaturated brine (200 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (PE/EA=50/1, 40/1) to afford tert-butylN-but-3-enyl-N-(2-oxobut-3-enyl)carbamate (1.40 g, 5.85 mmol, 49.16%yield) as yellow solid.

1.16.4 Preparation of Compound 6

To a mixture of tert-butyl N-but-3-enyl-N-(2-oxobut-3-enyl)carbamate(1.50 g, 6.27 mmol, 1.00 Eq) in DCM (250 mL), was added Zhan catalyst 1B(150.00 mg, 204.43 umol, 0.03 Eq) in one portion at 18° C. under N₂. Themixture was stirred at 18° C. for 10 hr. TLC showed the reaction wascompleted. The mixture was concentrated in vacuum. The residue waspurified by silica gel chromatography (PE/EA=30/1, 20/1) to affordtert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate (850.00 mg, 4.02mmol, 64.17% yield) as yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d)6.36-6.64 (m, 1H), 5.88-6.14 (m, 1H), 4.23-4.35 (m, 1H), 4.16 (s, 1H),3.51-3.68 (m, 2H), 2.62-2.78 (m, 2H), 1.46 (d, J=17.32 Hz, 1H)

1.16.5 Preparation of Compound 7

To a mixture of tert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate(540.00 mg, 2.56 mmol, 1.00 Eq) in BnOH (2.76 g, 25.56 mmol, 10.00 Eq),was added t-BuOK (28.68 mg, 255.61 umol, 0.10 Eq) in one portion underN₂. The mixture was stirred at 20° C. for 12 hours. LCMS showed thereaction was completed. The mixture was poured into water (100 mL) andstirred for 20 min. The aqueous phase was extracted with EA (40 mL*2).The combined organic phase was washed with saturated brine (20 mL*3),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toafford tert-butyl 5-benzyloxy-3-oxo-azepane-1-carboxylate (1.50 g,crude) as yellow oil.

1.16.6 Preparation of Compound 8

To a mixture of tert-butyl tert-butyl5-benzyloxy-3-oxo-azepane-1-carboxylate (700.00 mg, 2.19 mmol, 1.00 Eq)in EtOH (30 mL) was added NaBH₄ (99.49 mg, 2.63 mmol, 1.20 Eq) in oneportion under N₂. The mixture was stirred at 18° C. for 6 hours. TLCshowed the reaction was completed. The mixture was poured water (150 mL)and stirred for 20 min. The aqueous phase was extracted with EA (90mL*2). The combined organic phase was washed with saturated brine (80mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel chromatography (PE/EA=10/1, 2/1)to afford tert-butyl 5-benzyloxy-3-hydroxy-azepane-1-carboxylate (510.00mg, 1.59 mmol, 72.55% yield) as yellow oil, which was purified bypre-HPLC(FA) to afford 193 mg (D1) and 190 mg (D2).

1.16.7 Preparation of Compound 9

To a mixture of tert-butyl 5-benzyloxy-3-hydroxy-azepane-1-carboxylate(200.00 mg, 622.26 umol, 1.00 Eq, D2) in DCM (20 mL), was added DAST(200.60 mg, 1.24 mmol, 2.00 Eq) at −78° C. under N₂. The mixture wasstirred at −78° C. for 1 hr. TLC showed the reaction was completed. Themixture was poured into saturated NaHCO₃ (10 mL) and stirred for 5 min.The aqueous phase was extracted with DCM (10 mL*2). The combined organicphase was washed with NaClO₄ (5 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Petroleum ether/Ethyl acetate=15/1) to affordtert-butyl 5-benzyloxy-3-fluoro-azepane-1-carboxylate (163.00 mg, 504.02umol, 81.00% yield, D2) as yellow oil.

1.16.8 Preparation of Compound 10

To a solution of tert-butyl 5-benzyloxy-3-fluoro-azepane-1-carboxylate(163.00 mg, 504.02 umol, 1.00 Eq, D2) in MeOH (20 mL) was added Pd(OH)₂(30.00 mg, N/A) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 20° C. for 12 hours. TLC (Petroleum ether/Ethyl acetate=3:1) showedthe starting material was consumed completely. The reaction mixture wasfiltered and the filter was concentrated to give tert-butyl3-fluoro-5-hydroxy-azepane-1-carboxylate (115.00 mg, 492.97 umol, 97.81%yield, D2) as yellow oil.

1.16.9 Preparation of A28

To a mixture of tert-butyl 3-fluoro-5-hydroxy-azepane-1-carboxylate(115.00 mg, 492.97 umol, 1.00 Eq, D2) in DCM (3 mL), was added TFA (1mL) at 25° C. under N₂. The mixture was stirred at 25° C. for 2 hr. TLCshowed the reaction was completed. The mixture was concentrated invacuum to afford 6-fluoroazepan-4-ol (240.00 mg, crude, D2) as yellowoil.

1.17 Preparation of A29

1.17.1 Preparation of Compound 3

To a solution of Compound 1 (8.7 g, 65.7 mmol) in DMF (120 mL) was addedCompound 2 (3.5 g, 32.7 mmol) followed by K₂CO₃ (9.06 g, 65.7 mmol). Themixture was heated to 100° C. for 16 h. The mixture was diluted with EA(100 mL), and washed with H₂O (100 mL×3). The organic phase was driedover Na₂SO₄ and concentrated in vacuo to give the crude product, whichwas purified by column chromatography to give the desired product 3 ascolorless oil (5.1 g, 72.5%). LCMS: 256 [M+1].

1.17.2 Preparation of Compound 4

To a solution of Compound 3 (1.5 g, 6.97 mmol) in tolene (15 mL) wasadded CbzCl (1.42 g, 8.37 mmol). The mixture was heated to 110° C. for16 h. The mixture was concentrated in vacuo. The residue was dissolvedwith water and EA. The organic layer was washed with aq. Na₂CO₃, driedover Na₂SO₄ and concentrated in vacuo to give the crude product, whichwas purified by column chromatography to give the desired product 4 ascolorless oil (1.24 g, Yield: 68.9%). LCMS: 260 [M+1].

1.17.3 Preparation of Compound 5

To a solution of Compound 4 (1.0 g, 3.86 mmol) in DCM (60 mL) was addedDichloride Zhan catalyst 1B (150 mg, CAS: 918870-76-5). The mixture waspurged with N₂ for 10 min and stirred at 20° C. for 16 h. The mixturewas concentrated in vacuo to give the crude product, which was purifiedby column chromatography to give the desired product 5 as colorless oil(800 mg, Yield: 89.7%). LCMS: 232 [M+1].

1.17.4 Preparation of Compound 6

To a solution of compound 5 (800 mg, 3.46 mmol) in DCM (30 mL), wasadded m-CPBA (774 mg, 4.5 mmol). The mixture stirred at room temperaturefor 5 hours. The solution was quenched by aq. Na₂SO₃, and extracted withDCM (60 mL*2). The organic combined phase was dried over Na₂SO₄, andconcentrated to give desired compound 7 as colorless oil (812 mg, Yield:95.9%). LCMS: 248 [M+1].

1.17.5 Preparation of Compound 7

Compound 7 (812 mg, 3.31 mmol) was dissolved in MeOH (10 mL), thenconcentrated H₂SO₄ (200 mg) was added. The mixture stirred at roomtemperature for 1 h. The solution was neutralized with aq.Na₂CO₃ topH=7. The resulting mixture was concentrated in vacuo. The residue wasextracted with EA (60 mL*2). The combined organic phase was dried overNa₂SO₄, and concentrated in vacuo to give the crude product, which waspurified by column chromatography to give the desired product 8 ascolorless of (778 mg, Yield: 84.9%). LCMS: 280 [M+1].

1.17.6 Preparation of A29

To a solution of Compound 7 (778 mg, 2.8 mmol) in MeOH (70 mL) was addedPd(OH)₂/C (100 mg) under N₂. The mixture was stirred under H₂ balloon at23° C. for 2 h. The mixture was filtrated, the filtrate was concentratedto give the desired product 8 (310 mg, Yield: 78%).

1.18 Preparation of A20/A21

1.18.1 Preparation of Compound 2/2′

To a solution of Compound 1 (1.8 g, 5.8 mmol) in THF (40 mL) was addedBH₃.Me₂S (1.2 mL, 10 M) at 0° C., and the mixture was stirred at 16° C.for 12 h. To the reaction mixture was added NaOH (2.3 mL, 3 M) and H₂O₂(3.3 g, 29.0 mmol) at 0° C., and the mixture was stirred at 16° C. for12 h. The resulting mixture was quenched with Na₂SO₃ (Sat.) andextracted with EA (150 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give compound 2 and compound 2′ (1.8 g, crude),which was used in the next step directly.

1.18.2 Preparation of Compound 3/3′

To a solution of Compound 2 and Compound 2′(1.8 g, crude) in DCM (40 mL)was added Dess-Martin (3.5 g, 8.2 mmol) at 0° C., and the mixture wasstirred at 16° C. for 16 h. The resulting mixture was quenched withNa₂SO₃ (Sat.) and extracted with DCM (100 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the crude product,which was purified by flash column chromatography to give compound 3(0.58 g, 32%)¹H NMR (400 MHz, CDCl₃) δ=8.39-8.42 (m, 2H), 8.02-8.05 (m,2H), 3.73-3.78 (m, 1H), 3.60-3.65 (m, 2H), 3.51-3.56 (m, 2H), 3.38 (s,3H), 2.90-2.97 (m, 2H), 2.67-2.70 (m, 2H) and compound 3′ (0.86 g, 48%).¹H NMR (400 MHz, CDCl₃) δ=8.39-8.43 (m, 2H), 8.02-8.05 (m, 2H),4.04-4.09 (m, 1H), 3.72-3.77 (m, 1H), 3.64-3.68 (m, 2H), 3.38 (s, 3H),3.20-3.30 (m, 1H), 2.63-2.69 (m, 2H), 2.09-2.19 (m, 1H), 1.76-1.79 (m,1H).

1.18.3 Preparation of Compound 4′

To a solution of Compound 3′(0.86 g, 2.6 mmol) in EtOH (15 mL) was addedNaBH₄ (0.15 g, 3.9 mmol) at 0° C., and the mixture was stirred at 18° C.for 1 h. The resulting mixture was quenched with NH₄Cl (Sat.) andextracted with EA (100 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give compound 4′(0.86 g, crude), which was usedin the next step directly.

1.18.4 Preparation of Compound 5′

To a solution of Compound 4′(0.86 g, 2.6 mmol) in DMF (10 mL) was addedLiOH.H₂O (0.64 g, 15.6 mmol) and HSCH₂COOH (0.48 g, 5.3 mmol) at 0° C.,and the mixture was stirred at 16° C. for 2 h. Then Boc₂O (0.85 g, 5.3mmol) was added, and the mixture was stirred for another 1 h. Theresulting mixture was quenched with NaClO (aq.) and extracted with EA(100 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to give the crude product, which was purified by flash columnchromatography to give the desired product (0.39 g, 61%).

1.18.5 Preparation of A20

To a solution of Compound 5′(390 mg, 1.6 mmol) in DCM (5 mL) was addedTFA (3 mL) and stirred at 16° C. for 0.5 h. The reaction mixture wasconcentrated in vacuo to give the crude product (360 mg, contained TFA).

1.18.6 Preparation of Compound 4

To a solution of Compound 3 (0.58 g, 1.8 mmol) in EtOH (10 mL) was addedNaBH₄ (0.10 g, 2.7 mmol) at 0° C., and the mixture was stirred at 18° C.for 1 h. The resulting mixture was quenched with NH₄Cl (Sat.) andextracted with EA (100 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to the crude product, which was purified by flashcolumn chromatography to give the desired product (0.47 g, 81%).

1.18.7 Preparation of Compound 5

To a solution of Compound 4 (0.47 g, 1.4 mmol) in DMF (10 mL) was addedLiOH.H₂O (0.35 g, 8.5 mmol) and HSCH₂COOH (0.26 g, 2.8 mmol) at 0° C.,and the mixture was stirred at 16° C. for 2 h. Then Boc₂O (0.47 g, 2.1mmol) was added, and the mixture was stirred for another 1 h. Theresulting mixture was quenched with NaClO (aq.) and extracted with EA(100 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to give the crude product, which was purified by flash columnchromatography to give the desired product (0.20 g, 57%).

1.18.8 Preparation of A21

To a solution of Compound 5 (201 mg, 0.82 mmol) in DCM (3 mL) was addedTFA (3 mL) and stirred at 16° C. for 0.5 h. The reaction mixture wasconcentrated in vacuo to give the crude product (182 mg, TFA).

1.19 Preparation of Compound A34

1.19.1 Preparation of Compound 3

To a solution of Compound 1 (50.00 g, 310.17 mmol, 1.00 Eq) in DMF (500mL), the mixture was cooled to −10° C., then NaH (27.29 g, 682.37 mmol,2.20 Eq) was added, the mixture was stirred for 40 min at 0° C., andcompound 2 (38.77 g, 310.17 mmol, 1.00 Eq) was dropwised at −5˜0° C.,the mixture was stirred at 18° C. for 3 hr, TLC (PE:EA=3:1) shown thereaction was completed, the reaction solution was poured into ice-water,extracted with EA (200 mL) and the organic phase was washed with morewater (300*3), dried over NaSO4, concentrated, The residue was purifiedby silica gel chromatography (PE/EA=5/1) to afford Compound 3 (30.00 g,140.67 mmol, 45.35% yield) as yellow solid.

1.19.2 Preparation of Compound 4

To a solution of Compound 3 (1.00 g, 4.69 mmol, 1.00 Eq) in DCM (10 mL)was added m-CPBA (1.21 g, 7.04 mmol, 1.50 Eq), the mixture was stirredat 18° C. for 2 hr, TLC (PE:EA=3:1) shown the reaction was completed,the mixture was washed with NaSO₃ (30 mL*5), the organic phase was driedand concentrated, The residue was purified by silica gel chromatography(PE/EA=10/1) to afford compound 4 (700.00 mg, 3.05 mmol, 65.10% yield)as colorless oil. ¹H NMR (400 MHz, CDCl3) δ3.91-3.54 (m, 8H), 2.78-2.73(m, 2H), 1.48 (s, 9H).

1.19.3 Preparation of Compound 5

Compound 4 (600.00 mg, 2.62 mmol, 1.00 Eq) was added into HF-Et3N (15mL), the mixture was stirred at 18° C. for 12 hr, TLC (PE:EA=3:1) shownthe reaction was almost completed, the mixture was poured into icesat.NaHCO₃ (80 mL), extracted with EA (80 mL*2), washed with brine, Theresidue was purified by silica gel chromatography (PE/EA=7/1) to affordCompound 5 (190.00 mg, 762.20 umol, 29.09% yield) as colorless oil.

1.19.4 Preparation of Compound A34

Compound 5 (190.00 mg, 762.20 umol, 1.00 Eq) was added HCl-dioxane (5mL) and stirred for 30 min at 17° C., TLC (PE:EA=1:1) shown the reactionwas completed, the mixture was concentrated to give compound B (100.00mg, 670.42 umol, 87.96% yield).

1.20 Preparation of Compound A35/36

1.20.1 Preparation of Compound 2

To a solution of methylmagnesium bromide (2.5 M, 4.46 mL, 3.00 Eq) inTHF (30 mL) under N₂ at 0° C., was added compound 1 (800.00 mg, 3.72mmol, 1.00 Eq) and remained the temperature was 0-5° C., the mixture wasstirred at room temperature for 2 hr, TLC (PE:EA=3:1) shown the reactionwas almost completed, the solution was poured into ice sat.NH₄Cl (50mL), extracted with EA and concentrated. The residue was purified bysilica gel chromatography (PE/EA=5/1, to afford compound 2 (560.00 mg,2.42 mmol, 65.09% yield) as colorless oil.

1.20.2 Preparation of Compound A35

To a solution of compound 2 (560.00 mg, 2.42 mmol, 1.00 Eq) in MeOH (10mL) was added HCl-MeOH (10 mL), the mixture was stirred at roomtemperature for 30 min, TLC (PE:EA=1:1) shown the reaction wascompleted, the mixture was concentrated to give compound A (530.00 mg,crude) as a light yellow solid.

1.21 Preparation of A62

1.21.1 Preparation of Compound 3

To a solution of Vinylmagnesium Bromide (9.15 g, 69.69 mmol) in THF (20mL) was added Compound 1 (3.0 g, 13.94 mmol) under N₂ at −10° C. Thenthe mixture was stirred at 25° C. for 3 h. TLC monitored that thereaction completed. The mixture was poured into aq. NH₄Cl (300 mL) andstirred for 20 min. The aqueous phase was extracted with EA (100 mL*3).The combined organic phase were dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (PE/EA=6/1, 5/1) to afford the desired product compound 3(2.05 g, 8.43 mmol, 60.44%) as yellow oil.

¹H NMR (400 MHz, CDCl₃): δ ppm: 5.93 (dd, J=17.1, 10.7 Hz, 1H),5.39-5.56 (m, 1H), 5.19 (d, J=10.8 Hz, 1H), 3.63-3.97 (m, 5H), 3.08-3.59(m, 3H), 1.41-1.60 (m, 9H).

1.21.2 Preparation of Compound 4

To a solution of Compound 3 (500 mg, 2.06 mmol) in THF (10 mL) was addedBH₃/Me₂S (0.5 mL, 5.14 mmol, 10M) at 0° C., then warmed slowly to 25°C., and the reaction mixture was stirred at 25° C. for 12 h. Thesolution was poured into aq. NaOH (3.0 mL, 10.3 mmol, 3M), followed byH₂O₂ (1.17 g, 10.3 mmol, 30%) at 0° C. the mixture was stirred at 25° C.for 1 h, TLC monitored that the reaction was completed. The reactionmixture was washed by aq. Na₂SO₃ (50 mL*2), extracted by EA (80 mL*3).The organic layers were concentrated to give the crude product, whichwas purified by column chromatography (PE:EA=5:1, 2:1) to give thedesired product (210 mg, 39%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 3.31-4.02 (m, 9H), 3.06-3.29 (m, 2H),1.69-1.93 (m, 2H), 1.46-1.54 (m, 9H)

1.21.3 Preparation of Compound 5

To a solution of Compound 4 (210 mg, 0.8 mmol) in THF (8 mL) was addedNaH (48 mg, 1.2 mmol, 60%) at 0° C. After stirring for 30 min, asolution of MeI (0.8 mmol) in THF (2 mL) was added dropwise, and stirredat 25° C. for 2 h. TLC monitored that the reaction was completed. Themixture was poured into water and extracted with EA. The combinedorganic phase was dried over Na₂SO₄, and concentrated in vacuum. Theresidue was purified through column chromatography (PE/EA=5/1, 3/1) togive the desired product compound 5 (90 mg, 41%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 3.25-3.94 (m, 14H), 1.75-1.89 (m, 3H),1.43-1.56 (m, 9H)

1.21.4 Preparation of Amine A62

To a solution of compound 5 (350 mg, 1.27 mmol) in DCM (2 mL) was addedTFA (2 mL). The formed mixture was stirred for 2 h, and concentrated togive the desired product which was used for the next step directly (210mg, 94%).

1.22 Preparation of A37

1.22.1 Preparation of Compound 2

To a solution of compound 1 (400 mg, 1.84 mmol) in DCM (4 mL) added TEA(557.5 mg, 5.52 mmol), Ac₂O (376 mg, 3.69 mmol) followed by DMAP (44.9mg, 0.33 mmol). The mixture was stirred at 12° C. for 2 h. The mixturewas extracted with EA (50 mL*2). The combined organic layer was driedover Na₂SO₄, concentrated to give the crude product, which was purifiedby chromatography on silica gel to give compound 2 as colorless oil (450mg, 94.4%).

1.22.2 Preparation of A37

Compound 2 was treated with HCl/dioxane (4 M) to afford compound 3.

1.23 Preparation of A38-41

1.23.1 Preparation of Compound 2

To a solution of Compound 1 (2.36 g, 10.95 mmol) in DMF (23 mL) addedNaH (1.26 g, 31.5 mmol) portion-wise at 0° C. The mixture was attired at0° C. for 40 min. RX (219 mmol) added dropwise at 0° C. The mixture wasattired at 19° C. for 1 h. The mixture was poured into ice-water,extracted with EA. The combined organic layer was washed with H₂O, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified througha silica gel column to give Compound 2.

1.23.2 Preparation of A38-41

To a solution of Compound 2 (7.73 mmol) in Dioxane (2 mL) addedHCl/Dioxane (4M) (2 mL). The mixture was stirred at 19° C. for 1 h. Themixture was concentrated in vacuo to give Compound A38-41.

1.24 Procedure for Preparation of A42

1.24.1 Preparation of Compound 2

To a solution of Compound 1 (3.0 g, 13.9 mmol) in Toluene (30 mL) addedNa₂CO₃ (736.7 mg, 69.5 mmol) followed by [Ir(COD)Cl]₂ (189 mg, 0.28mmol). The mixture was degassed under vacuo and purged with N₂ severaltimes. Vinyl acetate (4.78 g, 55.5 mmol) added by syringe. The reactionmixture was heated to 110° C. for 16 h. The mixture was cooled to 11° C.and extracted with EA. The combined organic layer was dried over Na₂SO₄and concentrated. The residue was purified by column chromatography togive Compound 1 as colorless oil (1.0 g, 29.8%).

1.24.2 Preparation of Compound 3

To a solution of Compound 2 (1.0 g, 4.2 mmol) in THF (5.0 mL) addedPd(OAc)₂ (189.8 mg, 0.84 mmol), followed by CH₂N₂/Et₂O (100 mL). Themixture was stirred at 8° C. for 16 h. The mixture was quenched byaq.HCl (10 mL) (3N). The mixture was extracted with EA. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The residue wasdissolved in THF/H₂O (10 mL/10 mL) and added NaIO₄ (1.8 g, 8.4 mmol) andKOsO₄.2H₂O (66.2 mg, 0.21 mmol). The mixture was attired at 8° C. for 40min. The mixture was extracted with EA. The organic layer was washedwith aq.Na₂SO₃. The organic layer was dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by column chromatography PE:EA=15:1to give Compound 3 as brown oil (240 mg, 22.4%)

1.24.3 Preparation of A42

To a solution of Compound 3 (100 mg, 0.39 mmol) in DCM (2 mL) added TFA(2 mL). The mixture was stirred at 8° C. for 2 h. The mixture wasconcentrated in vacuum to give Compound 3 as brown oil (91 mg, crude).

1.25 Procedure for A43

1.25.1 Preparation of Compound 2

To a solution of compound 1 (10 g, 129.8 mmol) in DCM (150 mL) addedBoc₂O (28 g, 129.8 mmol) followed by TEA (19.7 g, 194.7 mmol). Themixture was stirred at 12° C. for 16 h. The mixture was concentrated togive the crude product, which was purified by chromatography on silicagel PE:EA (10:1) to give compound 2 as colorless oil (18.3 g, 79.9%).

1.25.2 Preparation of Compound 4

Compound 2 (1.0 g, 6.2 mmol) and compound 3 (960.8 mg, 10.5 mmol) inEtOH (12 mL) were cooled to 0° C. and treated with K₂CO₃ (960.8 mg, 6.96mmol). The mixture was stirred at 12° C. for 16 h. The mixture wasdiluted with EA (100 mL) and filtered through celite. The volatiles wereremoved under reduced pressure to give compound 4 as colorless oil (1.4g, 83.8%).

1.25.3 Preparation of Compound 5

To a solution of compound 4 (500 mg, 2.14 mmol) in DMF (6 mL) added NaH(246.7 mg, 6.4 mmol) portionwise at −5° C. After stirring for 30 min at0° C., the mixture was allowed to stir at 16° C. for 2 h. The mixturewas poured into ice-water with stirring, extracted with EA (30 mL*2).The combined organic layer was dried over Na₂SO₄, concentrated to givethe crude product, which was purified by chromatography on silica gelPE:EA (15:1) to give compound 5 as brown oil (140 mg, crude).

1.25.4 Preparation of A42

Compound 5 was treated with HCl/MeOH (4 M) to afford compound D.

1.26 Procedure for A44

1.26.1 Preparation of Compound 3

A mixture of Compound 1 (4.0 g, 37.3 mmol) and Compound 2 (10 g, 74.7mmol), K₂CO₃ (12.9 g, 93.4 mmol) in DMF (100 mL) was heated at 120° C.for 16 hrs. The mixture was poured into water (200 mL), extracted withEA (100 mL×3), and the organic layer was washed with brine (150 mL),dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby silica gel chromatography (PE:EA=1:1 to PE:EA=1:0) to give desiredcompound 3 (5.1 g, 63.5%) as brown oil.

1.26.2 Preparation of Compound 4

A solution of Compound 3 (5.1 g, 23.7 mmol) and CbzCl (4.4 g, 26.1 mmol)in toluene (100 mL) was heated at 110° C. for 16 hrs. Then the mixturewas concentrated to dryness, the residue was purified by silica gelchromatography (PE:EA=5:1 to PE:EA=2:1) to give desired compound 4 (4.5g, 72.5%) as brown oil.

1.26.3 Preparation of Compound 5

To a solution of Compound 4 (4.5 g, 17.3 mmol) in DCM (350 mL) was addedZhan Catalyst (22.1 mg, 0.86 mmol), the mixture was stirred at 25°C.-30° C. for 16 hour. The mixture was concentrated to dryness. Theresidue was purified by silica gel chromatography (PE:EA=20:1 toPE:EA=10:1) to give desired compound 5 (2.7 g, 71.5%) as a colorlessoil.

1.26.4 Preparation of Compound 6

A mixture of NaHCO₃ (2.43 g, 29.1 mmol) and RuCl₃ (200 mg, 1.08 mmol) inEA/MECN/H2O (72 ml/72 ml/12 ml) was added oxone (35.3 g, 58.0 mmol),then compound 5 (2.7 g, 11.6 mmol) was added into the above mixture. Andthe reaction was stirred at 40° C. for 10 min, the mixture was filteredand the filtrate was washed with Na₂SO₃ (100 ml), the organic layer wasdried over Na₂SO₄ and concentrated to dryness. The residue was purifiedwith column chromatography on silica gel (PE:EA=5:1 to 1:1) to givecompound 6 (1.7 g, 54.5%) as colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ=7.41-7.28 (m, 5H), 5.21-5.06 (m, 2H), 4.45 (t, J=10.0Hz, 1H), 4.32-4.16 (m, 1H), 4.16-4.00 (m, 2H), 3.84 (d, J=15.1 Hz, 1H),3.34-3.10 (m, 2H), 3.00-2.55 (m, 2H), 2.18-2.07 (m, 1H), 1.81-1.62 (m,1H)

1.26.5 Preparation of Compound 7

To a mixture of compound 6 (1.7 g, 6.50 mmol) in DCM (20 mL) was addedDMAP (1.2 g, 9.7 mmol) in one portion, followed by Ac₂O (0.8 g, 7.8mmol). The mixture was stirred at 40° C. for 16 h. The mixture wasconcentrated to dryness. The residue was purified with columnchromatography on silica gel (PE:EA=5:1 to 3:1) to give compound 7 (1.5g, 79.5%) as colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.43-7.30(m, 5H), 5.30-5.23 (m, 1H), 5.18-5.07 (m, 2H), 4.10-3.89 (m, 2H), 3.75(t, J=6.5 Hz, 1H), 3.53-3.30 (m, 2H), 2.89-2.61 (m, 2H), 2.04-1.90 (m,2H), 1.86 (td, J=3.3, 6.5 Hz, 1H)

1.26.6 Preparation of Compound 8

To a solution of compound 7 (1.7 g, 4.9 mmol) in DCM (15 mL) was added asolution of DAST (3.18 g, 19.6 mmol) in DCM (5 mL) drop-wise at −60° C.over a period of 30 mins under N₂. The reaction mixture was stirred at40° C. for another 12 hrs. TLC (PE:EtOAc=1:1) showed the startingmaterial was consumed completely. The reaction was poured into wasterand then extracted with DCM (50 mL*3). The combined organic phase waswashed with saturated brine (50 mL*2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography silica gel (PE/EA=3/1, 1/1) to afford compound 8(0.71 g, 44.31% yield) as yellow soil. ¹H NMR (400 MHz, CHLOROFORM-d)δ=7.42-7.30 (m, 5H), 5.25-5.14 (m, 3H), 3.75-3.58 (m, 2H), 3.52-3.33 (m,2H), 2.50-2.29 (m, 1H), 2.28-1.98 (m, 6H)

1.26.7 Preparation of Compound 9

To a mixture of compound 8 (770 mg, 2.35 mmol) in MeOH (10 mL) was addedK₂CO₃ (260 mg, 1.8 mmol) in one portion, the mixture was stirred at 40°C. for 1 h. The mixture poured into water (20 ml), extracted with EtOAc(20 ml), the combined organic layers were washed with brine (20 ml) andconcentrated to dryness to give compound 9 (560 mg, 83.3%).

1.26.8 Preparation of A44

To a solution of compound 9 (560 mg, 1.96 mmol) in MeOH (10 mL) wasadded Pd(OH)₂/C (10%, 56 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (50 psi) at 40° C. for 16 hours. TLC (PE:EtOAc=1:1) showed thestarting material was consumed completely. The reaction mixture wasfiltered and the filter was concentrated to give compound B (280 mg,95.53% yield) as yellow solid.

1.27 Preparation of A45

1.27.1 Preparation of Compound 3

To a mixture of compound 1 (20.00 g, 119.31 mmol, HCl salt) in MeOH (200mL) was added TEA (12.07 g, 119.31 mmol) and compound 2 (12.66 g, 119.31mmol, 1.00 Eq) in one portion at 16° C. The mixture was stirred at 16°C. for 16 h. The mixture was added NaBH₄ (2.71 g, 71.59 mmol)portion-wise at 0° C. The mixture was stirred at 16° C. for 1 h. Themixture was quenched by H₂O (50 mL). The mixture was concentrated andpurified by flash chromatography to give compound 3 as white solid(15.60 g, 50.73% yield).

1.27.2 Preparation of Compound 5

To a mixture of compound 3 (9.00 g, 31.27 mmol,) and compound 4 (3.73 g,31.27 mmol) in MeOH (90 mL)/H₂O (10 mL) was added Na₂CO₃ (3.98 g, 37.53mmol) followed by formalin (3.30 g, 40.66 mmol) in one portion at 16° C.under N₂. The mixture was stirred at 16° C. for 16 h. The mixture wasextracted with EA (400 mL*3). The combined organic phase was dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to afford compound5 as brown oil (8.90 g, 74.42%).

1.27.3 Preparation of Compound 7

To a mixture of Zn (3.08 g, 47.06 mmol) in THF (90 mL) was added TMSCl(2.68 g, 24.71 mmol, 1.05 Eq) slowly below 30° C. under N₂. The mixturewas stirred at 20° C. for 10 min. Compound 6 (5.25 g, 25.89 mmol, 1.10Eq) was added slowly below 30° C. under N₂. The mixture was stirred at20° C. for another 10 min. A solution of compound 5 (9.00 g, 23.53 mmol,1.00 Eq) in THF (10 mL) added slowly. While keep inner temperature wasbelow 30° C. The mixture was stirred at 20° C. for another 16 h. Themixture was quenched by aq.NaHCO₃ (5 mL). The precipitate was removed byfiltration. The filtrate was extracted with EA (100 mL*2). The combinedorganic phase was washed with 1M HCl (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography to afford compound 7 as colorless oil (4.00 g,44%).

1.27.4 Preparation of Compound 8

To a solution of compound 7 (4.00 g, 10.32 mmol) in THF (80 mL) wasadded t-BuOK (1.74 g, 15.49 mmol) in one portion at 15° C. The mixturewas stirred at 15° C. for 3 hr. The mixture was poured into aq.NH₄Cl andextracted with EA (10 mL*2). The combined organic phase was washed withsaturated brine (200 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to afford compound 8 as yellow oil (2.50 g, 70.97%).

1.27.5 Preparation of Compound 9

Compound 8 (2.50 g, 7.32 mmol) was dissolved in HCl (50 mL). The mixturewas heated to 100° C. and stirred for 16 hours. The mixture was cooledto 25° C. and concentrated in vacuo to afford compound 9 as brown oil(1.52 g, 72%).

1.27.6 Preparation of Compound 10

To a solution of compound 9 (1.52 g, 5.29 mmol) in MeOH (5 mL) was addedNaBH₄ (200.14 mg, 5.29 mmol) portion-wise at 0° C. The mixture wasstirred at 15° C. for 16 hr. Then the mixture was poured into aq.NH₄Cland extracted with EA (10 mL*2). The combined organic phase was driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to affordcompound 10 as yellow oil (1.39 g, 96.85%).

1.27.7 Preparation of Compound A45

To a solution of compound 10 (1.39 g, 5.12 mmol) in MeOH (60 mL) wasadded Pd(OH)₂/C (10%, 0.2 g) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 15° C. for 3 hours. TLC (PE:EtOAc=3:1) showed thestarting material was consumed completely. The reaction mixture wasfiltered and the filter was concentrated. The crude product was purifiedby silica gel chromatography to give compound A as colorless oil (511.00mg, 66.03%). 1.27 Preparation of A46

The procedure for preparation of amine B was the similar with amine A.LDA was used to cyclization step from compound 5 to compound 6.

1.28 Preparation of A47

1.28.1 Preparation of Compound 2

To a solution of compound 1 (5.00 g, 17.52 mmol,) in DMF (50 mL) wasadded K₂CO₃ (4.84 g, 35.04 mmol) followed by MeI (3.73 g, 26.28 mmol)portion-wise at 0° C. The mixture was stirred at r.t. for 16 hr. TLCshowed the reaction was completed. The mixture was cooled to r.t. andconcentrated in reduced pressure at 60° C. The residue was poured intoice-water (w/w=1/1) (150 mL) and stirred for 20 min. The aqueous phasewas extracted with EA (400 mL*3). The combined organic phase was washedwith saturated brine (200 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography to afford compound 2 as yellow solid (3.60 g, 68.64%).

1.28.2 Preparation of Compound 3

To a solution of compound 2 (15.00 g, 50.11 mmol, 1.00 Eq) in MeOH (100mL) was added KOH (5.62 g, 100.21 mmol, 2.00 Eq) in H₂O (35 mL). Themixture was heated to 60° C. for 3 hr. The mixture was cooled to r.t.and poured into aq.NH₄Cl. The mixture was extracted with EA (50 mL*3).The combined organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford compound 3 as brown oil (9.00 g,79.02%).

1.28.3 Preparation of Compound 4

To a solution of compound 3 (10.00 g, 43.99 mmol) in toluene (100 mL)was added t-BuOK (7.40 g, 65.99 mmol at 0° C. The mixture was stirred at15° C. for 16 hr. The mixture was extracted with EA. The EA layer waswashed with 10% aq.NaOH (50 mL*3). Combined the water layer and adjustPH=4 and extracted with EA (100 mL*3). The EA layer was dried overNa₂SO₄, filtered and concentrated in vacuum to afford compound 4 asyellow oil (10.00 g, 89.04%).

1.28.4 Preparation of Compound 6

To a solution of compound 4 (9.00 g, 35.25 mmol) in ACETONE (100 mL) wasadded K2CO3 (9.74 g, 70.50 mmol) followed by compound 5 (8.99 g, 52.88mmol). The mixture was refluxed at 60° C. for 16 hr. TLC showed thereaction was completed. The mixture was extracted with EA (100 mL*3).The combined organic layer was dried over Na₂SO₄, filtrated andconcentrated to give the residue product, which was purified by flashchromatography to give compound 6 as yellow oil (7.80 g, 74.41%).

1.28.5 Preparation of Compound 7

To a solution of diisopropylamine (6.18 g, 61.03 mmol) in THF (80 mL)was added n-BuLi (2.5 M, 22.19 mL) dropwise at −70° C. The mixture wasstirred at −10° C. for 30 min under N2. Compound 6 (5.50 g, 18.49 mmol)in THF (80 mL) was added dropwise at −70° C. When added completely, themixture was stirred at −30-−20° C. for 30 min. Then CH₃I (7.88 g, 55.48mmol, 3.00 Eq) was added dropwise at −70° C. The mixture was allowed tostir at 20° C. for 3 hr. TLC showed starting material was nearlyconsumed. The mixture was poured into aq.NH4Cl and extracted with EA (40mL*3). The combined organic phase was washed with saturated brine (20mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuumto the crude product, which was purified by flash chromatography toafford compound 7 as yellow oil (1.50 g, 26.07%).

1.28.6 Preparation of Compound 8

To a solution of compound 7 (800.00 mg, 2.6 mmol) in EtOH (10 mL) wasadded NaOH (205.69 mg, 5.22 mmol,) in H₂O (0.8 mL). The mixture wasstirred at 90° C. for 16 hr. TLC showed the starting material wasconsumed. The mixture was adjust pH=7 and extracted with DCM. Theorganic layer was concentrated in vacuum to give compound 8 (900.00 mg,crude).

1.28.7 Preparation of Compound 9

To a solution of compound 8 (900.00 mg, 3.73 mmol) in THF (10 mL) wasadded LiBH4 (243.72 mg, 11.19 mmol) in one portion at 0° C. The mixturewas stirred at 20° C. for 1 hr. Then the mixture was quenched byaq.NH4Cl and extracted with EA(50 mL*2). The combined organic phase wasdried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography to afford compound 9as yellow oil (570.00 mg, 62.80%).

1.28.8 Preparation of A47

Compound 5 was treated with HCl/dioxane (4 M) to afford compound B.

1.29 Preparation of A48/49:

1.29.1 Preparation of Compound 2

To a mixture of Mg (31.20 g, 1.30 mol) and I₂ (10 mmol) in THF (700 mL)was added compound 1 (130.00 g, 963 mmol) in THF (700 mL) dropwise at40° C. When added completely after 1.5 hr. The mixture was stirred at50° C. for 1 hr. Acetone (75.50 g, 1.30 mol) in THF (700 mL) was addeddropwise at −10° C. Then the mixture was stirred at 20° C. for another 2hr. The mixture was quenched by aq.NH4Cl and extracted with DCM (200mL). The mixture was distilled at ordinary pressure (190° C.) to affordcompound 2 as colorless oil (60.00 g, 52.55%).

1.29.2 Preparation of Compound 3

To a solution of compound 2 (7.00 g, 61.30 mmol) in TFA (104.84 g,919.50 mmol, 15.00 Eq) was added 2-chloroacetonitrile (13.88 g, 183.90mmol) in one portion. The mixture was heated to 70° C. for 16 hr. Themixture was adjust pH=7 with aq.Na₂CO₃ and extracted with EA. Theorganic layer was concentrated and purified by FLASH CHROMATOGRAPHY togive compound 3 as yellow oil (4.20 g, 36%).

1.29.3 Preparation of Compound 4

To a solution of compound 3 (4.20 g, 22.14 mmol) in EtOH (40 mL) wasadded THIOUREA (2.02 g, 26.57 mmol). The mixture was stirred at 100° C.for 2 hr. Then the mixture was detected by TLC. TLC showed SM wasconsumed. The mixture was added HOAc (8 mL) and heated to 90° C. for 16hours. The mixture was adjust PH=12 with aq.Na₂CO₃ and added CbzCl (7.55g, 44.28 mmol) The mixture was stirred at 25° C. for 2 hr. The mixturewas detected by TLC). TLC showed have DP. The mixture was extracted withEA (500 mL*2). The combined organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography to afford compound 4 as yellow oil (5.10 g,93.14%).

1.29.4 Preparation of Compound 6

To a solution of compound 4 (5.00 g, 20.22 mmol) in DMF (50 mL) wasadded NaH (1.37 g, 34.37 mmol) portion-wise at 0° C. under N₂. Whenadded completely. The mixture was stirred at 5° C. for 30 min. compound5 (4.89 g, 40.44 mmol, 2.00 Eq) was added dropwise at 0° C. The mixturewas stirred at 27° C. for 4 h. The mixture was detected by TLC. TLCshowed SM was consumed incompletely. The mixture was continued to stirat 27° C. for 2 hr. The mixture was poured into ice-water and extractedwith EA (200 mL*2). The combined organic layer was washed water (100mL*3) dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel chromatography to afford compound6 as yellow solid (3.20 g, 55.07%).

1.29.5 Preparation of Compound 7

To a solution of compound 6 (3.20 g, 11.13 mmol) in DCM (60 mL) wasadded Grubb's 2st (320.00 mg, 388.85 umol) under N₂. The mixture wasstirred at 28° C. for 16 hr under N2. The mixture was detected by TLC.TLC showed SM was consumed completely. The mixture was filtrated. Thefiltrate was concentrated in vacuum to give the residue, which waspurified by silica gel chromatography to afford compound 7 as yellow oil(2.70 g, 93.54%).

1.29.6 Preparation of Compound 8A, 8B

To a solution of compound 7 (2.70 g, 10.41 mmol) in THF (30 mL) wasadded BH3-Me2S (10 M, 3.12 mL) drop-wise at 0° C. under N₂. The mixturewas stirred at 29° C. for 16 hr. Then the mixture was added into aq.NaOH(2.08 g, 52.05 mmol, 5.00 Eq) in H₂O (4 mL) dropwise at 0° C. H2O2 (N/A,52.05 mmol, 5.00 Eq) was added into the mixture slowly. Then the mixturewas stirred at 29° C. for 3 hr. The mixture was detected by TLC. TLCshowed SM was consumed completely. The mixture was quenched by aq.Na₂SO₃and extracted with EA (60 mL*2). The combined organic layer was driedover Na₂SO₄, filtrated and concentrated in vacuum. The residue productwas purified by column chromatography to give compound 8A as colorlessoil (700.00 mg, 24.24%) and Compound 8B as colorless oil (1.20 g,41.56%).

1.29.7 Preparation of Compound A48

To a solution of f compound 8A (700.00 mg, 2.52 mmol) in MeOH (40 mL)was added Pd/C (10%, 80 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 27° C. for 2 hours. TLC (Petroleum ether/Ethylacetate=1:1) showed the starting material was consumed completely. Thereaction mixture was filtered and the filter was concentrated to givecompound A48 as yellow oil (320.00 mg, 88.66%).

Compound A49 was hydrogenated from 8B.

1.30 Preparation of A50

1.30.1 Preparation of Compound 2

To a solution of compound 1 (5.0 g, 44.2 mmol) in THF (100 mL) added NaH(2.6 g, 66.3 mmol) portionwise at −5° C., while keeping innertemperature between −5˜0° C. After stirring for 30 min at 0° C., BnBr(6.8 mL) was added dropwise. The mixture was stirred at 16° C. for 16 h.The mixture was poured into ice-water with stirring, extracted with EA(100 mL*2). The combined organic layer was dried over Na₂SO₄,concentrated to give the crude product, which was purified bychromatography on silica gel PE:EA(10:1) to give compound 2 as colorlessoil (6.3 g, 70.8%).

1.30.2 Preparation of Compound 3

To a solution of compound 2 (2.03 g, 10.0 mmol) in THF (50 mL) added LDA(10 mL) dropwise at −78° C. under N₂ atmosphere. After stirring for 1 hat −78° C., dimethyl carbonate (1.8 g, 20.0 mmol) was added dropwise at−78° C. The mixture was stirred at 16° C. for 2 h. The mixture wasquenched by aq.NH₄Cl, and extracted with EA (100 mL*2). The combinedorganic layer was dried over Na₂SO₄, concentrated to give the crudeproduct, which was purified by chromatography on silica gel PE:EA (1:1)to give compound 4 as colorless oil (800 mg, 30.6%).

1.30.3 Preparation of Compound 5

To a solution of LiAlH₄ (340 mg, 9.2 mmol) in THF (10 mL) was added asolution of compound 4 (800 mg, 3.06 mmol) in THF (10 mL) at −5° C.,while keeping inner temperature between −5˜10° C. The mixture wasstirred at 0° C. for 3 h. H₂O (0.5 mL) was added slowly, followed byNaOH (15%, 0.5 mL) and H₂O (1.5 mL). The resulting mixture wasfiltrated. The filtrate was extracted with EA (50 mL*2). The combinedorganic layer was dried over Na₂SO₄, concentrated to give compound 4 ascolorless oil (488 mg, 72.5%).

1.30.4 Preparation of Compound A50

To a solution of Compound 4 (488 mg, 2.23 mmol) in MeOH (60 mL) wasadded Pd(OH)₂ (10%, 50 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 Psi) at 12° C. for 16 h. The mixture was filtrated, the filtrateswas concentrated to give Compound A (220 mg, 76.6%).

1.31 Preparation of A51

1.31.1 Preparation of Compound 4

To a solution of Compound 1 (250 mg, 2.0 mmol) in DCM (5 mL) was addedTEA (0.3 mL) followed by Boc₂O (426 mg, 2.0 mmol). The mixture wasstirred at 12° C. for 2 h. The mixture was concentrated and purified byfish chromatography to give Compound 2 (350 mg, 76.6%).

1.31.2 Preparation of Compound 5

To a solution of Compound 3 (350 mg, 1.5 mmol) in DCM (5 mL) was addedDess-Martin reagent (190 mg, 1.95 mmol). The mixture was stirred at 12°C. for 2 h. The mixture was extracted with DCM (50 mL) and washed withaq.NaHSO3 several times and concentrated to give Compound 5 (410 mg,crude).

1.31.3 Preparation of Compound 4

To a solution of MeMgBr (1.8 mL, 3M) in THF (3 mL) was added a solutionof Compound 3 (410 mg, crude) in THF (3 mL) dropwise at 0° C. Themixture was stirred at 12° C. for 2 h. The mixture was quenched byaq.NH4Cl and extracted with DCM (50 mL), dried over Na₂SO₄ andconcentrated to give Compound 6 (340 mg, crude).

1.31.4 Preparation of Compound B

Compound 2 was treated with TFA/DCM(1:1) to afford compound B

1.32 Preparation of A52

To a solution of compound 1 (2.60 g, 8.69 mmol) in THF (30 mL) was addedLiBH4 (756.65 mg, 34.74 mmol) in one portion at 0° C. The mixture wasstirred at 15° C. for 16 hr. TLC showed the reaction was completed. Themixture was quenched by aq.NH₄Cl and extracted with EA (50 mL*3). Thecombined organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to afford compound 2 as colorless oil (2.10 g, 93.18%).The resulting solid was treated with HCl/dioxane to give HCl salt.

1.33 Preparation of A64

1.33.1 Preparation of Compound 2

To a mixture of 1-aminopropan-2-ol (10.00 g, 133.14 mmol, 1.00 eq) inDCM, was added Boc2O (29.06 g, 133.14 mmol, 1.00 eq) in one portion at30° C. under N₂. The mixture was stirred at 30° C. for 5 hours. TLCshowed the reaction was completed. The mixture was concentrated in toafford tert-butyl N-(2-hydroxypropyl) carbamate (23.00 g, 131.26 mmol,98.59% yield) as yellow oil.

1.33.2 Preparation of Compound 4

To a mixture of tert-butyl N-(2-hydroxypropyl)carbamate (5.00 g, 28.54mmol, 1.00 eq) in DMF (100.00 mL), was added NaH (2.51 g, 62.79 mmol,2.20 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0°C. for 1 hr, then 3-chloro-2-(chloromethyl)prop-1-ene (3.57 g, 28.54mmol, 1.00 eq) was added to the mixture, the mixture was stirred at 0°C. for 4 hr. TLC showed the reaction was completed. The mixture waspoured into water (100 mL) and stirred for 5 min. The aqueous phase wasextracted with ethyl acetate (100 mL*2). The combined organic phase waswashed with saturated brine (100 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Petroleum ether/Ethyl acetate=10/1) to affordtert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.20 g,9.68 mmol, 33.91% yield) as yellow oil.

1.33.3 Preparation of Compound 5

To a mixture of tert-butyl2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.40 g, 10.56 mmol,1.00 eq) in THF (50.00 mL), was added NaIO4 (4.97 g, 23.23 mmol, 2.20eq) and K2OSO4 (401.83 mg, 2.11 mmol, 0.20 eq) in one portion at 30° C.under N₂. The mixture was stirred at 30° C. for 5 hours. TLC showed thereaction was completed. The mixture was poured into saturated NaSO₃ (100mL) and stirred for 5 min. The aqueous phase was extracted with ethylacetate (30 mL*2). The combined organic phase was washed with saturatedbrine (30 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography(Petroleum ether/Ethyl acetate=8/1) to afford tert-butyl2-methyl-6-oxo-1,4-oxazepane-4-carboxylate (1.90 g, 8.29 mmol, 78.48%yield) as yellow oil.

1.33.4 Preparation of Compound 6

To a mixture of tert-butyl 2-methyl-6-oxo-1,4-oxazepane-4-carboxylate(1.90 g, 8.29 mmol, 1.00 eq) in EtOH (20.00 mL), was added NaBH4 (376.33mg, 9.95 mmol, 1.20 eq) in one portion at 30° C. under N₂. The mixturewas stirred at 30° C. for 5 hours. TLC showed the reaction wascompleted. The mixture was poured into saturated water (100 mL) andstirred for 5 min. The aqueous phase was extracted with ethyl acetate(30 mL*2). The combined organic phase was washed with saturated brine(30 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=5/1) to afford two point, the first point D1:494 mg;the second point D2:656 mg.

1.33.5 Preparation of A64

To a mixture of tert-butyl6-hydroxy-2-methyl-1,4-oxazepane-4-carboxylate (D1, 494.00 mg, 2.14mmol, 1.00 eq) in MeOH (5.00 mL), was added HCl/MeOH (15.00 mL) in oneportion at 30° C. under N₂. The mixture was stirred at 30° C. for 5hours. TLC showed the reaction was completed. The mixture wasconcentrated in vacuum to afford 2-methyl-1,4-oxazepan-6-ol (385.00 mg,crude) as yellow oil.

1.34 Preparation of A65

1.34.1 Procedure for Preparation of Compound 2

At ice bath, to a solution of Compound 1 (18 g, 0.24 mol) and Et3N (29g, 0.28 mol) in DCM (180 mL) was added Boc₂O (65 g, 0.28 mol). Then themixture was stirred at rt for 30 minutes.

Washed with water and concentrated to give the crude product, which waspurified by silica gel chromatography to give the desired product as awhite solid (38.1 g, 90.7%).

1.34.2 Procedure for Preparation of Compound 4

At ice bath, a solution of Compound 2 (3.5 g, 20 mmol) in DMF (30 mL)was added into a mixture of NaH (1.76 g, 44 mmol) in DMF (20 mL). Afterthe mixture stirring for 30 minutes, Compound 3 (2.5 g, 20 mmol) wasadded and stirred at rt for 2 hrs. Quenched with NH4Cl solution,extracted with EA, washed with water and concentrated to give the crudeproduct, which was purified by silica gel chromatography to give thepure product as an oil (780 mg, 17.2%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 4.94-5.10 (m, 2H), 4.29-4.53 (m, 3H),4.07 (d, J=10.0 Hz, 1H), 3.66-3.71 (m, 3H), 1.43 (m, 9H), 1.21 (d, J=7.1Hz, 3H).

1.34.3 Procedure for Preparation of Compound 5

A mixture of Compound 4 (780 mg, 3.43 mmol), K2OsO₄ (54 mg, 0.20 mmol)and NaIO4 (1.69 mg, 7.90 mmol) in THF—H₂O (1:1, 20 mL) was stirred at rtfor 2 hrs. The mixture was extracted with EtOAc (50 mL*2) and theorganic layer was concentrated to give the crude product as an oil (790mg).

1.34.4 Procedure for Preparation of Compound 6

A solution of Compound 5 (787 mg, 3.43 mmol) and NaBH4 (130 mg, 3.43mmol) in MeOH (15 mL) was stirred at rt for 30 minutes. Quenched withNH₄Cl solution, evaporated the solvent, extracted with EA (50 mL*2) andthe organic layer was concentrated to give the crude product, which waspurified by silica gel chromatography to give the desired product as anoil (517 mg, 65.2%).

¹H NMR (400 MHz, CDCl₃): δ ppm: 3.92-4.23 (m, 5H), 3.02-3.47.53 (m, 3H),1.50 (d, J=6.4 Hz, 9H), 1.01-1.04 (m, 3H).

1.34.5 Preparation of A65

4M HCl-dioxane (10 mL) was added to Compound 6 (500 mg, 2.16 mmol). Thenthe solution was stirred at rt for 30 minutes. The solvent wasevaporated in vacuo to give a HCl salt, which is used in the next stepdirectly.

1.35 Preparation of A66

1.35.1 Preparation of Compound 2

To a solution of compound 1 (10.00 g, 112.18 mmol, 1.00 Eq) in DCM (200mL) was added Et₃N (23.00 g, 227.30 mmol, 2.03 Eq). The mixture wascooled to 0° C. and Boc₂O (38.40 g, 175.95 mmol, 1.57 Eq) was added, themixture was stirred at 20° C. for 1 hr. The mixture was diluted with EAand washed with water. The organic phase was concentrated in vacuo. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=15/1) to afford compound 2 (16.00 g, 84.54 mmol, 75.36% yield)as white solid.

1.35.2 Preparation of Compound 4

To a solution of compound 2 (2.00 g, 10.57 mmol, 1.00 Eq) in DMF (60mL), the mixture was cooled to −10° C. Then NaH (930.16 mg, 23.25 mmol,2.20 Eq) was added, the mixture was stirred for 40 min at 0° C., andcompound 3 (1.59 g, 12.68 mmol, 1.20 Eq) was added dropwise at −5-0° C.The mixture was stirred at 20° C. for 3 hr. TLC (PE:EA=5:1) shown thereaction was completed. The reaction solution was poured into ice-water,extracted with EA and the organic phase was washed with more water,dried over Na₂SO4, and concentrated in vacuo. The residue was purifiedthrough silica gel chromatography (PE/EA=15/1) to afford compound 4(1.00 g, 4.14 mmol, 39.20% yield) as yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 5.02-4.98 (d, 2H), 4.15-4.08 (d, 4H), 3.64 (s, 2H), 1.47 (s,9H), 1.40 (s, 6H).

1.35.3 Preparation of Compound 5

To a mixture of compound 4 (1.00 g, 4.14 mmol, 1.00 Eq) in THF (5 mL)and H₂O (5 mL) was added NaIO₄ (2.04 g, 9.52 mmol, 2.30 Eq), followed byK₂OsO₄.2H₂O (76.18 mg, 207.00 umol, 0.05 Eq). The mixture was stirred at20° C. for 1 hr. TLC shown the reaction was completed. The reactionsolution was diluted with EA, washed with Na₂SO₃ and brine, the organicphase was concentrated to give product compound 5 (1.10 g, crude) asyellowed oil.

1.35.4 Preparation of Compound 6

To a solution of compound 5 (1.10 g, 4.52 mmol, 1.00 Eq) in MeOH (10 mL)was added NaBH₄ (512.97 mg, 13.56 mmol, 3.00 Eq) at 0° C. The mixturewas stirred at 20° C. for 1 h, TLC shown the reaction was completed, thereaction mixture was poured into ice sat.NH₄Cl and extracted with EA,the organic phase was concentrated, the residue was purified by silicagel chromatography (PE:EA=6:1) to give product compound 6 (700.00 mg,2.85 mmol, 63.13% yield) as colorless oil.

1.35.5 Preparation of A66

To a solution of compound 6 (700.00 mg, 2.85 mmol, 1.00 Eq) in dioxane(5 mL) was added HCl/dioxane (5 mL), the mixture was stirred at 23° C.for 1 hr. TLC shown the reaction was completed, the mixture wasconcentrated to give product compound D (600.00 mg, crude) as lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.45 (s, 1H), 3.93-3.92 (m, 2H),3.88-3.87 (m, 1H), 3.77-3.74 (m, 2H), 3.52-3.48 (m, 1H), 1.53-1.49 (m,6H).

1.36 Preparation of A52:

1.36.1 Preparation of Compound 2

A mixture of Compound I (1.0 g, 8.6 mmol) and NH₂OH.HCl (3.0 g, 43mmol), AcONa (2.1 g, 25.8 mmol) in EtOH/H₂O (20 mL/20 mL) was stirred at25° C. for 1 hour. Then the mixture was extracted with EA (150 mL×3),the organic layer was dried over Na₂SO₄, and concentrated to givecompound 2 (1.0 g, 89.2%).

1.36.2 Preparation of Compound 3

To a solution of compound 2 (1.0 g, 7.6 mmol) in acetone/H₂O (20 mL/20mL) was added TsCl (2.16 g, 11.4 mmol) and Na₂CO₃ (1.2 g, 23.2 mmol).The resulting mixture was stirred at 60° C. for 16 hours. The mixturewas concentrated to remove solvents. The residue was extracted with EA(20 mL×3). The organic layer was dried over Na₂SO₄, filtered, thefiltrates were concentrated to give compound 3 (740 mg, 74%) as whitesolid.

1.36.3 Preparation of A52

To a suspension of LiAlH₄ (200 mg, 5.2 mmol) in THF (5 mL) was addedcompound 3 (370 mg, 2.8 mmol). The mixture was stirred at 60° C. for 2hours. The reaction was quenched with H₂O (0.2 mL), dried over Na₂SO₄,filtered, and the filtrates were concentrated to give desired compound 4(250 mg, 75.7%) as a yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d)6=3.08-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.89-2.82 (m, 1H), 2.81-2.66 (m,5H), 2.00-1.85 (m, 2H)

1.37 Preparation of A68:

1.37.2.1 Preparation of Compound 2

To a solution of Compound 1 (45.00 g, 265.93 mmol, 1.00 Eq) in THF (225mL) and H₂O (450 mL) was added NMO (71.65 g, 611.64 mmol, 2.30 Eq) andOsO₄ (500.00 mg, 1.97 mmol, 0.01 Eq), the mixture was stirred at 28° C.for 16 hr. TLC showed the reaction was completed. The reaction solutionwas diluted with EA, washed with sat.Na₂SO₃ and brine. The organic phasewas concentrated in vacuo. The residue was purified by silica gelchromatography (PE:EA=3:1) to give compound 2 (33.00 g, 162.38 mmol,61.06% yield). ¹H NMR (400 MHz, CHLOROFORM-d) ppm 4.23 (d, J=2.38 Hz,2H), 3.52-3.63 (m, 2H), 3.34 (t, J=12.11 Hz, 2H), 3.13 (br, 1H), 2.97(br, 1H), 1.45 (s, 9H).

1.37.2.2 Preparation of Compound 4

To a solution of Compound 2 (33.00 g, 162.38 mmol, 1.00 Eq) in DCM (330mL) was added [acetoxy(phenyl)-iodanyl]acetate (78.45 g, 243.57 mmol,1.50 Eq) at 0° C., the mixture was stirred for 1 hr from 0° C. to 28° C.Then the mixture was cooled to −60° C. and bromo(vinyl)magnesium (1 M,974.28 mL, 6.00 Eq) in THF was added, the mixture was stirred for 2 hrfrom −60° C. to 28° C. TLC showed the reaction was completed, themixture was diluted with EA and washed with sat.NH4Cl and brine. Theorganic phase was concentrated, the residue was purified by silica gelchromatography (PE:EA=10:1) to give Compound 4 (17.00 g, 66.06 mmol,40.68% yield) as colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) ppm5.73-5.92 (m, 2H), 5.25-5.40 (m, 2H), 5.16 (dd, J=10.48, 1.19 Hz, 2H),4.22-4.50 (m, 2H), 3.56-3.75 (m, 1H), 3.38 (d, J=11.17 Hz, 2H),2.82-2.98 (m, 1H), 1.42-1.53 (m, 9H).

1.37.2.3 Preparation of Compound 5_Trans and 5_Cis

To a solution of Compound 4 (13.00 g, 50.52 mmol, 1.00 eq) in DCM (1.80L) was added Zhan catalyst 1B (1.20 g, 1.64 mmol, 0.03 eq) under N₂, themixture was stirred at 30° C. for 30 hr. TLC showed the reaction wascompleted, the reaction mixture was concentrated, the residue waspurified by silica gel chromatography (PE:EA=2:1) to give both cisisomer 5_Cis (2.80 g, 12.22 mmol, 24.22% yield) with lower polarity andtrans isomer 5_Trans (2.80 g, 12.22 mmol, 24.22% yield) with higherpolarity.

5_Cis: ¹HNMR (400 MHz, CHLOROFORM-d) ppm 5.83 (d, J=1.63 Hz, 2H)4.26-4.43 (m, 2H) 3.67 (d, J=13.55 Hz, 2H) 3.38 (dd, J=13.68, 8.28 Hz,2H) 1.48 (s, 9H).

5_Trans: ¹H NMR (400 MHz, CHLOROFORM-d) ppm 5.82 (s, 2H) 4.46 (br. s.,2H) 3.53-3.79 (m, 3H) 3.34-3.46 (m, 1H) 1.48 (s, 9H).

1.37.2.4 Preparation of 6_Cis

To a solution of Compound 5_Cis (2.80 g, 12.21 mmol, 1.00 eq) in MeOH(100.00 mL) was added Pd/C (300.00 mg) under Ar. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (50 psi) at 30° C. for 16 hours. TLC showed thereaction was completed. The mixture was filtered and the filtrate wasconcentrated, the residue was purified by silica gel chromatography(PE:EA=1:1) to give compound 6_Cis (1.50 g, 6.49 mmol, 53.12% yield) ascolorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 3.95-4.08 (m, 2H)3.68-3.85 (m, 2H) 3.25 (ddd, J=14.56, 9.98, 4.08 Hz, 2H) 3.10 (br, 1H)2.02 (br, 1H) 1.84-1.98 (m, 2H) 1.66-1.76 (m, 2H) 1.49 (s, 9H).

1.37.2.5 Preparation of A68_Cis

To a solution of Compound 6_Cis (500.00 mg, 2.16 mmol, 1.00 eq) indioxane (10.00 mL) was added HCl dioxane (20.00 mL), the mixture wasstirred at 30° C. for 2 hr, TLC showed the reaction was completed, themixture was concentrated to give A68_Cis (250.00 mg, 1.91 mmol, 88.24%yield) as yellow solid.

A68_Trans was prepared from compound 5_Trans through the same procedure.

Part II General Procedure for Targets General Procedure A

1.1 General Procedure for Preparation of Compound 2

A mixture of Compound 1 (4.53 mmol) in SOCl₂ (10 mL) was heated toreflux overnight. The mixture was concentrated to give the crudeproduct, which was used for the next step directly.

1.2 General Procedure for Preparation of Compound 3

To a boiled solution of Compound 2 (1.08 g, 4.52 mmol) in toluene (10mL) was added aniline (4.52 mmol), and refluxed for 2 h. The mixture wasconcentrated in vacuo to give a solid, which was used for the next stepdirectly.

1.3 General Procedure for Preparation of iii

To a solution of Compound 3 (0.3 mmol) in MeCN (3 mL) was added amine(0.3 mmol) and Et₃N (30 mg, 0.33 mmol) at rt, and the mixture wasstirred at rt for 2 h. The mixture was diluted with CH₂Cl₂ (20 mL) andwashed with water. The organic phase was concentrated in vacuo to givethe crude product, which was purified by prep-HPLC to give the desiredproduct.

General Procedure B

1.1 Preparation of Compound 2

A mixture of compound 1 (9.5 g, 0.04 mol), NBS (8.3 g, 0.044 mol) and(PhCO)₂O (1.9 g, 8 mmol) in CCl₄ (100 mL) was heated to reflux for 5hours. Then the mixture was concentrated under vacuum, and the residuewas purified by column chromatography (PE:AcOEt=20:1) to give thecompound 2 (4 g, 31%).

1.2 Preparation of Compound 3

A mixture of compound 2 (1 g, 3.24 mmol) and AcOK (3.18 g, 32.4 mmol) inacetone (20 mL) was stirred for 18 hours. Then the mixture was filteredand washed with acetone. The filtrate was concentrated under vacuum togive the compound 3 (0.7 g, 78%). 1H NMR (400 MHz, CDCl₃) δ 8.26 (d,J=1.6 Hz, 1H), 7.99-8.01 (m, 1H), 7.48-7.50 (d, J=8 Hz, 1H), 5.24 (s,2H), 3.95 (s, 3H), 2.19 (s, 3H).

1.3 Preparation of Compound 4

A mixture of compound 3 (7.5 g, 0.026 mol), PMBSH (5.25 g, 0.034 mol),Pd₂(dba)₃ (3.65 g, 5.2 mmol), Xantphos (3 g, 5.2 mmol) and DIPEA (6.7 g,5.2 mmol) in 1,4-dioxane (80 mL) was heated to 100° C. for 18 hours.Then the mixture was concentrated under vacuum, and purified by columnchromatography (PE:AcOEt=10:1) to give the compound 4 (6.9 g, 73%). 1HNMR (400 MHz, CDCl₃) δ 8.08 (d, J=1.6 Hz, 1H), 7.86-7.89 (m, 1H),7.42-7.44 (d, J=8 Hz, 1H), 7.19-7.21 (m, 2H), 6.81-6.84 (m, 2H), 5.17(s, 2H), 4.13 (s, 2H), 3.94 (s, 3H), 3.80 (s, 3H), 2.13 (s, 3H).

1.4 Preparation of Compound 5

A mixture of compound 4 (3.60 g, 10 mmol) and LiOH (4.20 g, 100 mmol) inTHF/H₂O (50 mL/10 mL) was heated to 60° C. for 14 hours. The reactionmixture was adjusted to pH=6.0 with HCl (1N), extracted with AcOEt. Theorganic phase was dried over Na₂SO₄ and concentrated to give thecompound 5 (2.40 g, 80%). 1H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=1.2 Hz,1H), 7.87-7.89 (m, 1H), 7.56-7.58 (d, J=8 Hz, 1H), 7.17-7.20 (m, 2H),6.81-6.83 (m, 2H), 4.65 (s, 2H), 4.12 (s, 2H), 3.74 (s, 3H).

1.5 Preparation of Compound 6

To a solution of compound 5 (1.0 g, 3.4 mmol) in THF (20 mL) was addedTEA (1.0 mg, 10 mmol) and AcCl (540 mg, 6.8 mmol) at 0° C. The resultingmixture was stirred at rt for 14 hours. The mixture was diluted withwater, and extracted with AcOEt. The organic phase was dried overNa₂SO₄, concentrated under vacuum to give the crude product, used in thenext step directly.

1.6 Preparation of Compound 7

A mixture of compound 6 (100 mg, 0.28 mmol), HATU (126 mg, 0.33 mmol),DIPEA (164 g, 0.43 mmol), 3-chloro-4-fluoroaniline (63 mg, 0.43 mmol) inDMF (5 mL) was stirred at rt for 4 hours. The mixture was diluted withAcOEt and water, and combined organic layers were separated, dried overNa₂SO₄ and concentrated. Then the residue was purified by columnchromatography (PE:AcOEt=5:1) to give the compound 5 (110 m g, 74%).

1H NMR (400 MHz, CD₃OD) δ 7.96-7.99 (m, 2H), 7.79 (d, J=1.6 Hz, 1H),7.49-7.51 (d, J=8 Hz, 1H), 7.16-7.28 (m, 3H), 6.80-6.82 (m, 2H), 5.16(s, 2H), 4.17 (s, 2H), 3.74 (s, 3H), 2.11 (s, 3H).

1.7 Preparation of Compound 8

To a solution of compound 7 (150 mg, 0.32 mmol) in MeCN (8 mL), AcOH(0.1 mL) and H₂O (0.2 mL) was added1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (89 mg, 0.45 mmol) at−15° C. and stirred for 4 hours. Then the mixture was diluted with waterand extracted with DCM. The combined organic layer was dried over Na₂SO₄and concentrated in vacuo to give a crude product (134 mg, crude), useddirectly in the next step.

1.8 Preparation of iiii

To a solution of compound 8 (134 mg, 0.32 mmol, crude) in MeCN (2 mL)was added TEA (106 mg, 1.05 mmol) and amine (0.84 mmol). The resultingmixture was stirred at rt until the starting material was consumed.Then, to the resulting mixture was added a mixture of LiOH (150 mg, 3.6mmol) in MeOH/H₂O (2 mL/0.5 mL) and stirred for 14 hours. The mixturewas diluted with water, and extracted with EA. The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The residue waspreparative HPLC to give the product.

General Procedure C

1.1 Preparation of Compound 2

To a solution of methyl 3-bromo-4-hydroxy-benzoate (1.00 g, 4.33 mmol,1.00 eq) in toluene (15.00 mL) were added vinyl acetate (745.54 mg, 8.66mmol, 2.00 eq), Chloro(1,5-cyclooctadiene)iridium(I) dimer (29.08 mg,43.30 umol, 0.01 eq) and Na₂CO₃ (229.47 mg, 2.17 mmol, 0.50 eq). Themixture was stirred at 100° C. for 16 hr under N₂ protection. TLCdetected the reaction was complete, the solvent was evaporated, theresidue was purified by chromatography (silica gel, eluting withPE:EA=10:1) to afford product methyl 3-bromo-4-vinyloxy-benzoate (730.00mg, 2.84 mmol, 65.58% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ8.29 (d, J=1.76 Hz, 1H), 7.99 (dd, J=8.53, 2.01 Hz, 1H), 7.06 (d, J=8.53Hz, 1H), 6.65 (dd, J=13.80, 6.02 Hz, 1H), 4.98 (dd, J=13.80, 2.01 Hz,1H), 4.70 (dd, J=5.90, 1.88 Hz, 1H), 3.93 (s, 3H).

1.2 Preparation of Compound 3

To a solution of methyl 3-bromo-4-vinyloxy-benzoate (1.00 g, 3.89 mmol,1.00 eq) in DCM (15.00 mL) was added ZnEt₂ (960.91 mg, 7.78 mmol, 2.00eq) at 0° C. under N₂ protection. Then the mixture was stirred at 0° C.for 30 min, and ClCH₂I (1.72 g, 9.73 mmol, 2.50 eq) was added. Theformed mixture was stirred at 25° C. for 16 hrs. The mixture was pouredinto NH₄Cl solution, and extracted with EA, the combined organic layerwas dried over Na₂SO₄, concentrated, the residue was diluted in THF(5.00 mL) and H₂O (5.00 mL), NaIO₄ (832.00 mg, 3.89 mmol, 1.00 eq) andK₂OsO₄ (74.01 mg, 389.00 umol, 0.10 eq) was added, the mixture wasstirred at 25° C. for 30 min, then the reaction was quenched bysaturated Na₂SO₃, extracted with EA, the combined organic layer wasdried over Na₂SO₄, concentrated, the residue was purified by silica gelchromatography (PE:EA=10:1) to afford product methyl3-bromo-4-(cyclopropoxy)benzoate (530.00 mg, 1.95 mmol, 50.26% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=2.01 Hz, 1H), 8.00(dd, J=8.78, 2.01 Hz, 1H), 7.28-7.33 (m, 1H), 3.92 (s, 3H), 3.88 (t,J=4.39 Hz, 1H), 0.76-0.99 (m, 4H).

1.3 Preparation of Compound 4

To a solution of methyl 3-bromo-4-(cyclopropoxy)benzoate (530.00 mg,1.95 mmol, 1.00 eq) and (4-methoxyphenyl)methanethiol (451.12 mg, 2.93mmol, 1.50 eq) in toluene (10.00 mL) were added Pd₂(dba)₃ (89.28 mg,97.50 umol, 0.05 eq), Xantphos (112.83 mg, 195.00 umol, 0.10 eq) andDIPEA (504.04 mg, 3.90 mmol, 2.00 eq) under N₂ protection. Then themixture was stirred at 100° C. for 16 hr N₂ protection. TLC detected thereaction was complete, the solvent was evaporated, the residue waswashed with water, the aqueous layer was extracted with EA, the combinedorganic layer was dried over Na₂SO₄, concentrated, the residue waspurified by silica gel chromatography (PE:EA=5:1) to afford productmethyl 4-(cyclopropoxy)-3-[(4-methoxyphenyl)methylsulfanyl]benzoate(600.00 mg, 1.74 mmol, 89.34% yield) as white solid. LCMS: 345 [M+1].

1.4 Preparation of Compound 5

To a suspension of methyl4-(cyclopropoxy)-3-[(4-methoxyphenyl)methylsulfanyl]benzoate (1.00 g,2.90 mmol, 1.00 eq) in MeCN (8.00 mL), AcOH (100.00 uL) and H₂O (200.00uL) at −15° C. was added1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (914.17 mg, 4.64 mmol,1.60 eq), the mixture was stirred at −15° C. for 2 hours. The residuewas washed with water, the aqueous layer was extracted with EA, thecombined organic layer was dried over Na₂SO₄, concentrated to affordcrude product, which was used in the next step directly.

1.1.5 Preparation of Compound 7

To a solution of methyl 3-chlorosulfonyl-4-(cyclopropoxy)benzoate(840.00 mg, crude, 2.89 mmol, 1.00 eq) in MeCN (10.00 mL) were added1,4-oxazepan-6-ol (338.49 mg, 2.89 mmol, 1.00 eq) and TEA (584.88 mg,5.78 mmol, 2.00 eq). The resulting mixture was stirred at 28° C. untilthe starting material was consumed. The solvent was removed and theresidue was purified by chromatography (silica gel, eluting withPE:EA=3:1) to give desired compound methyl4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoate(620.00 mg, 1.67 mmol, 57.76% yield) as white solid. LCMS: 372 [M+1].

1.6 Preparation of Compound 8

To a solution of methyl4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoate(620.00 mg, 1.67 mmol, 1.00 eq) in THF (5.00 mL) and H₂O (1.00 mL). Theformed mixture was stirred at 50° C. for 3 hr. The reaction mixture wasneutralized with 1N HCl solution and extracted with EA, the combinedorganic layer was dried over Na₂SO₄, concentrated to afford crudeproduct4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid(510.00 mg, 1.43 mmol, 85.45% yield) as white solid.

1.7 Preparation of Compound 2081

To a solution of4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzoic acid(170.00 mg, 475.68 umol, 1.00 eq) and 3-chloro-4-fluoro-aniline (69.24mg, 475.68 umol, 1.00 eq) in DMF (5.00 mL) were added HATU (180.87 mg,475.68 umol, 1.00 eq) and DIPEA (122.95 mg, 951.36 umol, 2.00 eq). Themixture was stirred at 25° C. for 16 hr. TLC detected the reaction wascomplete, the mixture was poured into water, extracted with EA, thecombined organic layer was dried over anhydrous Na2SO4, concentrated,the residue was purified by prep-HPLC (FA) to afford productN-(3-chloro-4-fluoro-phenyl)-4-(cyclopropoxy)-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzamide(94.10 mg, 194.05 umol, 40.79% yield) as white solid. ¹H NMR (400 MHz,MeOD) δ 8.48 (d, J=2.01 Hz, 1H), 8.23 (dd, J=8.66, 2.13 Hz, 1H), 7.96(dd, J=6.78, 2.51 Hz, 1H), 7.70 (d, J=8.78 Hz, 1H), 7.59-7.65 (m, 1H),7.27 (t, J=8.91 Hz, 1H), 4.07-4.13 (m, 1H), 4.03 (t, J=6.53 Hz, 1H),3.77-3.97 (m, 4H), 3.61-3.73 (m, 2H), 3.21-3.30 (m, 1H), 3.11 (dd,J=14.56, 7.53 Hz, 1H), 0.84-1.04 (m, 4H). LCMS: 485/487 [M+1].

2082/2083 were prepared through the same procedure as 2081.

General Procedure D

1.1 Preparation of Compound 2

A mixture of 4-bromo-3-chlorosulfonyl-benzoic acid (6.90 g, 23.04 mmol,1.00 Eq) in SOCl₂ (27.41 g, 230.40 mmol, 10.00 Eq) was stirred at 80° C.for 3 hr. Then the solvent was evaporated. The residue was diluted inTOLUENE (50 mL), and MeOH (959.66 mg, 29.95 mmol, 1.30 Eq) was added,the formed mixture was stirred at 110° C. for 2 hr. Solid was formed,and the solvent was evaporated, the solid was washed with PE, andfiltered to afford product methyl 4-bromo-3-chlorosulfonyl-benzoate(7.22 g, 23.03 mmol, 99.94% yield) as white solid.

1.2 Preparation of Compound 4

To a solution of methyl 4-bromo-3-chlorosulfonyl-benzoate (7.22 g, 23.03mmol, 1.00 Eq) in DCM (100 mL) was added azepan-4-ol (2.65 g, 23.03mmol, 1.00 Eq) and TEA (2.33 g, 23.03 mmol, 1.00 Eq). The resultingmixture was stirred at 25° C. until the starting material was consumed.The solvent was removed and the residue was purified by silica gelchromatography (PE:EA=1:1) to give desired compound methyl4-bromo-3-(4-hydroxyazepan-1-yl)sulfonyl-benzoate (7.00 g, 17.85 mmol,77.49% yield). LCMS: 393/395 [M+1].

1.3 Preparation of Compound 5

To a mixture of methyl 4-bromo-3-(4-hydroxyazepan-1-yl)sulfonyl-benzoate(1.00 g, 2.55 mmol, 1.00 Eq) in DMF (15 mL), was added NaH (153.00 mg,3.82 mmol, 1.50 Eq) in portions at 0° C. under N₂. The mixture wasstirred at 25° C. for 30 min. Then bromomethylbenzene (654.19 mg, 3.82mmol, 1.50 Eq) was added and stirred at 25° C. for 16 hours. TLC showedthe reaction was completed. The mixture was poured into NH₄Cl aqueousand extracted with EA. The combined organic phase was washed withsaturated brine, dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography(eluting with PE/EA=10/1, 2/1) to afford methyl3-(4-benzyloxyazepan-1-yl)Sulfonyl-4-bromo-benzoate (550.00 mg, 1.14mmol, 44.71% yield) as white solid. LCMS: 482/484 [M+1].

1.4 Preparation of Compound 6

Methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-bromo-benzoate (1.30 g, 2.69mmol, 1.00 Eq), allyl(tributyl)stannane (1.07 g, 3.23 mmol, 1.20 Eq)LiCl (136.83 mg, 3.23 mmol, 1.20 Eq) and Pd(PPh3)4 (310.85 mg, 269.00umol, 0.10 Eq) in TOLUENE (20 mL) was de-gassed and then heated to 110°C. for 16 hr under N₂. TLC (PE:EtOAc=1:1) showed the starting materialand the product was the same spot. The reaction mixture was poured intoH₂O, extracted with EA. The organic phase was dried over anhydrousNa₂SO₄, concentrated in vacuum to give a residue, which was purified bycolumn chromatography (silica gel, eluting with PE:EA=1:1) to afford thepure methyl 4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00mg, 1.42 mmol, 52.80% yield) as light yellow solid.

1.5 Preparation of Compound 7

To a solution of methyl4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00 mg, 1.42mmol, 1.00 Eq) in THF (10 mL) and H₂O (2 mL) were added OsO₄ (36.10 mg,142.00 umol, 0.10 Eq) and NaIO₄ (607.45 mg, 2.84 mmol, 2.00 Eq) at 0° C.The mixture was stirred at 25° C. for 3 hr. TLC detected the reactionwas complete, the mixture was poured into saturated Na₂S₂O₃ solution,extracted with DCM, the combined organic layer was dried over anhydrousNa₂SO₄, concentrated, the residue was diluted in MeOH (10 mL), to theformed mixture was added NaBH₃CN (88.86 mg, 1.41 mmol, 1.00 Eq). Themixture was stirred at 25° C. for 3 hr. TLC detected the reaction wascomplete, the reaction was quenched with water, extracted with EA, thecombined organic layer was dried over anhydrous Na₂SO₄, concentrated,the residue was purified by chromatography (silica gel, eluting withPE:EA=3:1 to 1:1) to afford product methyl3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-hydroxyethyl)benzoate (340.00mg, 759.71 umol, 53.88% yield). LCMS: 448 [M+1].

1.6 Preparation of Compound 8

To a solution of methyl3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-hydroxyethyl)benzoate (340.00mg, 759.71 umol, 1.00 Eq) in MeCN (10 mL) were added PBSF (458.86 mg,1.52 mmol, 2.00 Eq), N,N-diethylethanamine; trihydrofluoride (244.95 mg,1.52 mmol, 2.00 Eq) and TEA (307.50 mg, 3.04 mmol, 4.00 Eq). The mixturewas stirred at 28° C. for 16 hr under N₂ protection. TLC detected thereaction was complete, the mixture was poured into water, extracted withEA, the combined organic layer was dried over anhydrous Na₂SO₄,concentrated, the residue was purified by chromatography (silica gel,eluting with PE:EA=1:1) to afford product methyl3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoate (180.00 mg,400.42 umol, 52.71% yield) as colorless oil.

1.7 Preparation of Compound 9

To a solution of methyl3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoate (180.00 mg,400.42 umol, 1.00 Eq) in THF (5 mL) and H₂O (1 mL). The formed mixturewas stirred at 25-50° C. for 3 hr. The reaction mixture was neutralizedwith 1N HCl solution and concentrated to give the crude product3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoic acid (160.00mg, 367.39 umol, 91.75% yield).

1.8 Preparation of Compound 10

To a solution of3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-fluoroethyl)benzoic acid (80.00mg, 183.69 umol, 1.00 Eq) and aniline (202.06 umol, 1.10 Eq) in MeCN (5mL) were added HATU (76.83 mg, 202.06 umol, 1.10 Eq) and DIEA (47.48 mg,367.38 umol, 2.00 Eq). The mixture was stirred at 25° C. for 16 hr. TLCdetected the reaction was complete, the mixture was poured into water,extracted with EA, the combined organic layer was dried over anhydrousNa2SO4, concentrated, the residue was purified by prep-TLC (eluting withPE:EA=2:1) to afford product3-(4-benzyloxyazepan-1-yl)sulfonyl-N-(3-chloro-4-fluoro-phenyl)-4-(2-fluoroethyl)benzamide(65.00 mg, 115.44 umol, 62.85% yield) as white solid.

1.9 Preparation of 2205/2206

To a solution of3-(4-benzyloxyazepan-1-yl)sulfonyl-N-(3-chloro-4-fluoro-phenyl)-4-(2-fluoroethyl)benzamide(65.00 mg, 115.44 umol, 1.00 Eq) in MeOH (15 mL) was added Pd/C (30.00mg, 115.44 umol, 1.00 Eq) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ at 25° C. for 16 hr. TLC showed the starting material was consumedcompletely. The reaction mixture was filtered and the filter wasconcentrated, purified by prep-TLC (eluting with PE:EA=1:1) to affordproductN-(3-chloro-4-fluoro-phenyl)-4-(2-fluoroethyl)-3-(4-hydroxyazepan-1-yl)sulfonyl-benzamide(24.00 mg, 50.75 umol, 43.96% yield) as white solid.

General Procedure E

1.1 Preparation of Compound 2

To a solution of Compound 1 (6.0 g, 21.6 mmol) in MeOH (80 mL) was addedSOCl₂ (10.2 g, 86.5 mmol) at 0° C. under N₂. The reaction mixture washeated to 85° C. for 3 h. The resulting mixture was concentrated invacuo to give compound 2 (6.2 g, crude), which was used for the nextstep directly. ¹H NMR (400 MHz, DMSO) δ=8.17-8.19 (m, 1H), 8.03-8.05 (m,2H), 3.88 (s, 3H).

1.2 Preparation of Compound 3

A mixture of compound 2 (5.6 g, 19.2 mmol), PMBSH (3.8 g, 24.7 mmol),Pd₂(dba)₃ (1.7 g, 1.9 mmol), Xantphos (2.2 g, 3.8 mmol) and DIPEA (4.9g, 38.0 mmol) in 1,4-dioxane (100 mL) was heated to 100° C. for 16 h.The reaction mixture was concentrated under vacuum, and purified bycolumn chromatography to give the compound 3 (3.9 g, 56%).

1.3 Preparation of Compound 4

To a solution of compound 3 (1.2 g, 3.3 mmol) in MeCN/HOAc/H₂O(16/0.2/0.4, mL) was added1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.97 g, 4.9 mmol) at−15° C. and stirred for 3 h. The reaction mixture was diluted with waterand extracted with EA. The combined organic layer was dried over Na₂SO₄and concentrated in vacuo to give a crude product, which was used in thenext step directly (1.0 g, crude).

1.4 Preparation of Compound 6

To a solution of Compound 4 (1.0 g, 3.2 mmol) in MeCN (10 mL) was addedCompound 5 (553 mg, 4.8 mmol) and Et₃N (810 mg, 8.0 mmol) at 25° C. andstirred for 1 h. The mixture was diluted with EA (100 mL) and washedwith water (80 mL). The organic phase was concentrated in vacuo to givethe crude product, which was purified by flash column chromatography togive the desired product (0.54 g, 43%). LCMS: 392.0 [M+1].

1.5 Preparation of Compound 8

A mixture of compound 6 (540 mg, 1.4 mmol), compound 7 (261 mg, 2.1mmol), Cs₂CO₃ (898 mg, 2.8 mmol) and Pd(dppf)Cl₂ (140 mg, 0.2 mmol) inTHF/H₂O (10/1, mL) was heated to 80° C. for 16 h. The reaction mixturewas diluted with EA (100 mL), and washed with brine (60 mL). The organicphase was concentrated under vacuum to give a crude product, which wasused in the next step directly (451 mg, crude).

1.6 Preparation of Compound 9

A mixture of compound 8 (451 mg, 1.4 mmol) and NaOH (112 mg, 2.8 mmol)in THF/H₂O (5/1, mL) was heated to 35° C. for 16 h. The reaction mixturewas diluted with water (80 mL), and extracted with EA (80 mL). Theaqueous phase was adjusted to pH=6.0 with HCl (2 M), and extracted withEA (80 mL). The organic phase was dried over Na₂SO₄ and concentrated togive the crude product, which was used in the next step directly (305mg, 71%).

1.7 Preparation of 2018

A mixture of compound 9 (143 mg, 0.46 mmol), HATU (209 mg, 0.55 mmol),DIPEA (119 mg, 0.92 mmol), compound 9 (80 mg, 0.55 mmol) in MeCN (5 mL)was heated to 50° C. for 3 h. The mixture was diluted with EA (80 mL),and washed with water (60 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo to give the crude product, which was purifiedPrep-HPLC to give the desired product (149.64 mg, 74%). LCMS: 441.0[M+1].

General Procedure F

1.1 Preparation of Compound 2

To a solution of Compound 1 (5 g, 0.023 mol) in SOCl2 (30 mL) was addedMeOH (1.104 g, 0.035 mol) under 0° C. And the solution was stirred at80° C. for 2 h. Then the solution was cooled to 18° C. and concentratedto remove the solvent. It was washed with water (20 mL) and extractedwith EA (100 mL), dried over Na₂SO₄, concentrated to give compound 2(5.3 g, 93.8%).

LCMS: 229 [M+1]

1.2 Preparation of Compound 3

A solution of Compound 2 (5.3 g, 0.023 mol) in CCl4 (50 mL) was addedNBS (3.72 g, 0.021 mol), BPO (557 mg, 0.002 mol) in one portion underN2. The mixture was heated to 80° C. for 2 h. The mixture was washedwith saturated Na₂SO₃ (50 mL) and extracted with EA (100 mL*2). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuum.The residue was purified by PE to give compound 3 (6.2 g, crude).

1.3 Preparation of Compound 4

To a solution of Compound 3 (6.2 g, 0.02 mol) in MeCN (100 mL) was addedCsF (18.35 g, 0.121 mol), 18-Crown-6 (1.06 g, 4.03 mmol) in one portionand it was heated to 90° C. for 16 hours. The mixture was filtered andconcentrated in reduced pressure at 40° C. The residue was purified bycolumn chromatography on silica gel (PE/EA=30/1, 20/1, 10/1) to givecompound 4 (360.00 mg, 7.24% for two steps) as solid. ¹H NMR (400 MHz,METHANOL-d₄)=8.16-8.10 (m, 1H), 8.05-7.99 (m, 1H), 7.86-7.80 (m, 1H),5.54-5.49 (m, 1H), 5.42-5.37 (m, 1H), 3.95 (s, 3H).

1.4 Preparation of Compound 5

To a solution of Compound 4 (0.36 g, 1.46 mmol) in 1,4-dixoane (40 mL)was added PMBSH (0.338 g, 2.19 mmol), DIPEA (0.337 g, 2.92 mmol),Xantphos (42.24 mg, 0.073 mmol) at 18° C. Then Pd₂(dba)₃ (66.85 mg,0.073 mmol) was added to the solution and it was heated to 120° C. for16 h. The mixture solution was concentrated and purified by columnchromatography on silica gel (PE/EA=30/1, 20/1, 10/1) to give compound 5(0.464 g, 99.2%)

LCMS: 321 [M+1]

1.5 Preparation of Compound 6

To a solution of compound 5 (0.464 g, 1.45 mmol) in THF (20 mL) wasadded a solution of LiOH (694.55 mg, 29.00 mmol) in H₂O (5 mL). Themixture solution was heated to 60° C. for 2 h. The solution was adjustedto pH<3 by adding HCl (3M). Then it was extracted by EtOAc (200 mL),dried over Na₂SO₄, concentrated to give compound 6 (0.5 g, crude).

LCMS: 307 [M+1].

1.6 Preparation of Compound 8

To a solution of compound 6 (0.5 g, 1.63 mmol) in DCM (20 mL) was addedDIPEA (0.421 g, 3.26 mmol), HATU (0.93 g, 2.45 mmol). The mixturesolution was stirred at 20° C. for 1 h. Then compound 7 (0.285, 1.96mmol) was added to the mixture and it was stirred at 20° C. for 16hours. The solution was washed with saturated NH₄Cl (50 mL), extractedby EtOAc (100 mL*2), dried over Na₂SO₄, concentrated to give crudeproduct which was purified by column chromatography on silica gel(PE/EA=20/1, 10/1, 3/1) to give compound 8 (0.7 g, 98.97%)

LCMS: 435 [M+23]

1.7 Preparation of 2207-2208

To a solution of compound 8 (100 mg, 0.23 mmol) in MeCN/AcOH/H2O (10 mL,80:1:2) was added DCDMH (90.81 mg, 0.46 mmol) under −5° C. It wasstirred at −5° C. for 2 h. Then amine (0.35 mmol), Et₃N (69.96 mg, 0.69mmol) was added to the solution. It was stirred at 18° C. for 0.5 h.Then it was concentrated to give crude product which was purified bypre-HPLC to give desired product.

General Procedure G

Preparation of 2032 is Exemplified:

1.1 Preparation of Compound 2

To HSO₃Cl (80 mL) was added Compound 1 (20.0 g, 0.13 mol) portionwise at0° C., then the resulting mixture was heated to 140° C. for 4 hours.After cooled to room temperature, the mixture was poured into ice-water.The resulting precipitate was collected by filtration and dried to givedesired compound 2 (25.0 g, 76%) as white solid.

1.2 Preparation of Compound 3

Compound 2 (3.0 g, 11.7 mmol) was added to a mixture of HNO₃ (4 mL) inH₂SO₄ (20 mL), and heated to 90° C. for 4 hours. After cooled to roomtemperature, the mixture was added to ice-water slowly. The resultingprecipitate was collected by filtration and dried to give desiredCompound 3 (1.3 g, 38%) as white solid. ¹H NMR (CDCl₃, 400 MHz): δ 9.05(d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H).

1.3 Preparation of Compound 4

A mixture of Compound 3 (1.3 g, 4.3 mmol) and SOCl₂ (40 mL) was heatedto 90° C. for 4 hours. The mixture was concentrated in vacuo. Theresidue was dissolved with toluene (10 mL) and heated to 90° C.3-chloro-4-fluoroaniline (1.2 mg, 3.9 mmol) was added and the mixturewas continued to heat to reflux for 4 hours. The mixture wasconcentrated to give desired compound 4 (1.6 g, crude) as yellow solid,which was used for the next step without further purification.

1.4 Preparation of Compound 6

To a mixture of Compound 4 (0.8 g, crude) and 5 (256 mg, 1.8 mmol) inCH₃CN (10 mL), was added Et₃N (566 mg, 5.6 mmol), and stirred at roomtemperature for 4 hours. The mixture was diluted with EA (50 mL), theorganic layer was washed with NH₄Cl (50 mL*2) and concentrated to givedesired compound 6 (0.5 g, crude) as a yellow solid, which was used forthe next step without further purification.

1.5 Preparation of Compound 7

To a solution of Compound 6 (0.1 g, crude) in MeOH (10 mL) was addedammonia (0.5 mL, 28%), and the mixture was heated to 70° C. for 4 hours.The mixture was concentrated in vacuo to give desired compound 7 (80 mg,crude) as yellow solid, which was used for the next step withoutpurification.

1.6 Preparation of Compound 8

A mixture of Compound 7 (80 mg, crude), Fe (62 mg, 1.1 mmol) and NH₄Cl(59 mg, 1.1 mmol) in MeOH—H₂O (10 mL/2 mL) was heated to 70° C. for 4hours. The mixture was filtered and washed with EA (50 mL). The filtratewas washed with saturated NH₄Cl (50 mL*2) and concentrated to givedesired compound 8 (75 mg, crude) as white solid, which was used for thenext step without purification.

1.7 Preparation of 2032

A mixture of Compound 8 (75 mg, crude) in formic acid (10 mL) wasmicrowaved to 110° C. for 10 mins. The mixture was concentrated invacuo. The residue was dissolved in MeOH—H₂O (10 mL/2 mL), and K₂CO₃ (57mg, 0.4 mmol) was added. The mixture was heated to 80° C. for 2 hours.After LCMS showed the reaction was finished, the mixture wasconcentrated in vacuo and extracted with EA. The organic phase wasconcentrated in vacuo and the residue was purified via acid prep-HPLC togive 2032 (65.89 mg, yield 64.2%) as a white solid.

General Procedure H

Preparation of 2619_D2, 2626_D2 Exemplified:

To a solution ofN-(3-chloro-4-fluoro-phenyl)-3-(3,6-dihydroxyazepan-1-yl)sulfonyl-4-fluoro-benzamide(300.00 mg, 650.93 umol, 1.00 eq), TEA (65.87 mg, 650.93 umol, 1.00 eq)and DMAP (79.52 mg, 650.93 umol, 1.00 eq) in DCM (30.00 mL), wasdropwise added acetyl chloride (51.10 mg, 650.93 umol, 1.00 eq) at 0° C.The mixture was stirred for 1 hr. LCMS showed 30% 2433_D2 and 32%2626_D2 produced, and 25% starting material remained. The reactionmixture was washed with water. The organic layer was dried andconcentrated. The residue was purified by pre-HPLC to give 2619_D2(95.00 mg, 188.90 umol, 29.02% yield) as white solid and 2626_D2 (90.00mg, 165.15 umol, 25.37% yield) as white solid.

General Procedure I

Preparation of 2632, 2634 Exemplified:

1 Procedure for Preparation of 2632

1.1 General Scheme:

1.1.1 Preparation of 2638

To a solution ofN-(3-chloro-4-fluoro-phenyl)-3-(3,6-dihydroxyazepan-1-yl)sulfonyl-4-fluoro-benzamide(500.00 mg, 1.08 mmol, 1.00 eq) in MeCN (30.00 mL) were added1H-TETRAZOLE (455.98 mg, 6.51 mmol, 6.00 eq) andN-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (1.12 g, 3.25 mmol,3.00 eq). The mixture was stirred at 30° C. for 2 hr. Then H₂O₂ (737.94mg, 6.51 mmol, 6.00 eq) was added, and the mixture was stirred at 30° C.for 16 hr. TLC showed the material was remained, and ˜1/3 desiredproduct detected. The mixture was poured into saturated Na₂SO₃ (20 mL),extracted with ethyl acetate (20 mL*3), the combined organic layer wasdried over anhydrous Na₂SO₄, concentrated in vacuum. The residue waspurified by chromatography (silica gel, eluting with Petroleumether/Ethyl acetate=10/1˜1/2) to afforddibenzyl[1-[5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-fluoro-phenyl]sulfonyl-6-hydroxy-azepan-3-yl]phosphate(105.00 mg, 139.22 umol, 12.89% yield, 95.61% purity) as white solid. ¹HNMR (400 MHz, MeOD) δ 8.46 (dd, J=6.59, 2.26 Hz, 1H), 8.23-8.31 (m, 1H),7.98 (dd, J=6.78, 2.45 Hz, 1H), 7.60-7.68 (m, 1H), 7.52 (t, J=9.32 Hz,1H), 7.20-7.43 (m, 11H), 5.07 (d, J=9.04 Hz, 4H), 4.63 (br. s., 1H),3.92 (br. s., 1H), 3.71-3.85 (m, 2H), 3.18 (dd, J=15.07, 7.16 Hz, 1H),2.98 (dd, J=14.32, 7.54 Hz, 1H), 1.96-2.09 (m, 1H), 1.72-1.90 (m, 3H).LCMS: 721/723 [M+1].

1.1.2 Preparation of Compound 2632

To a solution ofdibenzyl[1-[5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-fluoro-phenyl]sulfonyl-6-hydroxy-azepan-3-yl]phosphate(210.00 mg, 291.22 umol, 1.00 eq) in MeOH (10.00 mL) was added LiCl(12.34 mg, 291.22 umol, 1.00 eq) and Pd/C (10%, 20 mg) under N₂atmosphere. The suspension was degassed and purged with H₂ for 3 times.The mixture was stirred under H₂ (15 Psi) at 15° C. for 1 hour. TLCshowed the material was consumed completely. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bypre-HPLC (FA) to afford product1-((5-((3-chloro-4-fluorophenyl)carbamoyl)-2-fluorophenyl)sulfonyl)-6-hydroxyazepan-3-yl dihydrogen phosphate (110.30 mg, 192.35umol, 66.05% yield, 94.32% purity) as white solid. ¹H NMR (400 MHz,MeOD) δ 8.49 (dd, J=6.65, 2.13 Hz, 1H), 8.21-8.31 (m, 1H), 8.02 (dd,J=6.65, 2.64 Hz, 1H), 7.61-7.70 (m, 1H), 7.52 (t, J=9.29 Hz, 1H), 7.27(t, J=8.91 Hz, 1H), 4.58 (br. s., 1H), 3.87-4.13 (m, 3H), 3.03 (dd,J=14.56, 7.78 Hz, 1H), 2.88 (dd, J=13.80, 9.03 Hz, 1H), 2.10 (dd,J=11.67, 6.15 Hz, 1H), 1.80-2.01 (m, 3H). LCMS: 527/529 [M+1].

2 Procedure for Preparation of 2634

2.1 General Scheme:

2.1.1 Preparation of Compound 1893i

A solution ofN-(3-chloro-4-fluoro-phenyl)-4-fluoro-3-[(6-hydroxy-1,4-oxazepan-4-yl)sulfonyl]benzamide(500.00 mg, 1.12 mmol, 1.00 eq) andN-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (772.99 mg, 2.24mmol, 2.00 eq) in MeCN (7.50 mL) was added 2H-tetrazole (0.45 M, 7.46mL, 3.00 eq). The mixture was stirred at 25° C. for 4 hr. Then H₂O₂(152.22 mg, 1.34 mmol, 3.00 eq) was added, the reaction was stirred at25° C. for 1 hr. TLC showed the reaction was completed. The mixturequenched by saturated Na₂SO₃ (10 mL), extracted with EA (20 mL*3), thecombined organic layer was dried over anhydrous Na₂SO₄, concentrated.The residue was purified by chromatography (silica gel, eluting withPE:EA=2:1 to 1:1) to afford productdibenzyl[4-[5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-fluoro-phenyl]sulfonyl-1,4-oxazepan-6-yl]phosphate(1.00 g, 1.41 mmol, 89.92% yield) as white solid. ¹H NMR (400 MHz, MeOD)δ 9.86 (brs, 1H), 8.42 (dd, J=6.53, 2.26 Hz, 1H), 8.13-8.26 (m, 1H),7.95 (dd, J=6.53, 2.51 Hz, 1H), 7.71 (dt, J=7.15, 4.20 Hz, 1H),7.24-7.39 (m, 10H), 7.11 (t, J=8.78 Hz, 1H), 5.07 (t, J=9.66 Hz, 2H),4.91-5.01 (m, 2H), 4.40 (d, J=6.27 Hz, 1H), 3.73-3.98 (m, 5H), 3.57-3.69(m, 2H), 3.32 (dd, J=13.18, 6.40 Hz, 1H). LCMS: 707/709 [M+1].

2.1.2 Preparation of 2634

To a solution ofdibenzyl[4-[5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-fluoro-phenyl]sulfonyl-1,4-oxazepan-6-yl]phosphate(1.00 g, 1.41 mmol, 1.00 eq) in MeOH (20.00 mL) was added LiCl (60 mg,1.41 mmol, 1.00 eq), followed by Pd/C (15.00 mg) under N2. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 25° C. for 1 hours. LCMSshowed the reaction was completed. The reaction mixture was filtered andthe filter was concentrated. The residue was purified by pre-HPLC (FA)to afford[4-[5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-fluoro-phenyl]sulfonyl-1,4-oxazepan-6-yl]dihydrogenphosphate (433.00 mg, 821.90 umol, 58.29% yield) as white solid. ¹H NMR(400 MHz, MeOD) δ 9.14 (s, 1H), 8.51 (d, J=4.52 Hz, 1H), 8.23 (brs, 1H),8.04 (dd, J=6.59, 2.45 Hz, 1H), 7.63-7.75 (m, 1H), 7.50 (t, J=9.32 Hz,1H), 7.25 (t, J=8.95 Hz, 1H), 4.49 (brs, 1H), 3.79-4.07 (m, 5H), 3.70(t, J=8.85 Hz, 1H), 3.34-3.47 (m, 2H). LCMS: 527/529 [M+1].

Resolution of Chiral Compounds

Chiral resolution of selected compounds of the invention was performedaccording to the conditions listed in Table 3.

TABLE 3 Compound Supercritical Fluid Chromatography Structure IDResolution condition

1763 Column: AD-10 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:0.1% NH₃H₂O in EtOH Gradient (% B): 30% Flow Rate: 60 g/min. Wavelength:220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elution time (min):6.3-7.5; 8.3-10.0

1763_E1

1763_E2

1766 Column: AD-5 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:0.1% NH₃H₂O in IPA Gradient (% B): 30% Flow Rate: 60 g/min. Wavelength:220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elution time (min):5.2-6.8; 7.2-8.9

1766_E1

1766_E2

1821 Column: AD-10 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:0.1% NH₃H₂O in EtOH Gradient (% B): 30% Flow Rate: 60 g/min. Wavelength:220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elution time (min):3.6-4.2; 4.6-5.6

1821_D1

1821_D2

1822 Column: AD-10 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:0.1% NH₃H₂O in EtOH Gradient (% B): 30% Flow Rate: 60 g/min. Wavelength:220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elution time (min):8.9-11.0; 11.9-14.6

1822_D1

1822_D2

1829 Column: AD-5 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:30% 0.1% NH₃H₂O in IPA Gradient (% B): 40% Flow Rate: 60 g/min.Wavelength: 220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elutiontime (min): 5.9-7.4; 7.9-9.7

1829_D1

1829_D2

1893 Column: AD-10 um (CHIRAL PAK) Mobile Phase A: CO₂ Mobile Phase B:0.1% NH₃H₂O in MeOH Gradient (% B): 40% Flow Rate: 70 g/min. Wavelength:220 nm Column Temp.: 35° C. Back Pressure: 100 Bar Elution time (min):4.5-5.1; 5.5-6.5

1893_E1

1893_E2

Example HBV Assembly Assay

The fluorescence quenching in vitro assembly HBV assay was developedaccording to a method described by Zlotnick and coworkers (NatureBiotechnology 2006, 24:358). The assay is based on the observation thatthe C-termini of the HBV core protein cluster together during capsidformation. This assay utilizes a mutant C150 HBV capsid protein whereall wild-type cysteines are mutated to alanines, but a C-terminalcysteine residue is preserved and is labeled with fluorescent BoDIPY-FLdye. HBV C150Bo protein is highly fluorescent, however the fluorescenceis drastically reduced during the capsid assembly process. Thus, theassay measures the ability and potency of test compounds to modulatecapsid assembly by monitoring the fluorescence of the labeled capsidC150Bo protein.

In a typical assay, the mutant HBV C150 protein (amino acids 1-150,C49A, C61A, C107A, 150C) is cloned into a T7 RNA-polymerase basedexpression vector, expressed in E. coli and purified to homogeneity as adimer. The purified HBV core protein is desalted and labeled withBODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-wellplate format. The assembly reactions are carried out in 50 mM Hepesbuffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with theHBV CA protein for 15 min, and the assembly reactions are initiated byaddition of NaCl. The reaction is allowed to continue for 1 hour at roomtemperature.

To determine the effect on capsid assembly, each test compound isinitially screened at least 4 different concentrations in duplicates.Primary hits are compounds that show activity in the assembly assay at10 uM. Identified primary hits are confirmed in follow-up studies asdescribed elsewhere herein. Known modulators of HBV CA assembly, such asHAP-1 and BAY 41-4109, are used as control compounds in theseexperiments and exhibited EC₅₀ values consistent with the literature.EC₅₀ values for test compounds are determined via analysis of thedose-response curve.

Selected compounds of the invention were assayed in the HBV assemblyassay, as described above. The assembly assay was conducted in 96-wellplate format. The assembly reactions were carried out in 50 mM Hepesbuffer, pH 7.5 and 150 mM NaCl. The compounds were pre-incubated withthe HBV CA protein for 15 min, and the assembly reactions were initiatedby addition of NaCl. The reaction was allowed to continue for 1 hour atroom temperature. The 96-well plate assembly assay consistently had Z′factors greater than 0.7 and were robust and reproducible both fromplate-to-plate and day-to-day.

To determine the effect on capsid assembly, each test compound wasinitially screened at 5 different concentrations: about 30 μM, 10 μM, 3μM, 1 μM, and 0.3 μM in duplicates. Primary hits were compounds thatshow >50% activity in the assembly assay at about 10 μM and arepresentative group of these active compounds is shown in Table 4.

TABLE 4 HBV assembly assay (‘+’ indicates >50% activity at about 10 μM)Compound Activity 1763_E1 + 1763_E2 + 1765 + 1766_E1 + 1766_E2 + 1768 +1769 + 1819 + 1820 + 1821 + 1821_D1 + 1821_D2 + 1822_D1 + 1822_D2 +1826_D2 + 1829_D1 + 1829_D2 + 1829-2 + 1890 + 1891 + 1892 + 1893 +1893_E1 + 1893_E2 + 1894 + 1895 + 1909 + 1910 + 1914 + 1915 + 1916 +1917 + 1919 + 1938 + 1944 + 1975 + 1977 + 1979 + 1980 + 1981 + 1983 +1986 + 1987 + 1989 + 2002 + 2004 + 2007 + 2024 + 2033 + 2114_D1 +2114_D2 + 2121 + 2123 + 2199 + 2202 + 2205 + 2206 + 2433_D1 + 2433_D2 +2492 + 2505 + 2547 + 2548 + 2550 + 2617_D2 + 2618_D1 + 2618_D2 +2619_D2 + 2625_D2 + 2626_D2 +

Example Inhibition of HBV Replication Dot-Blot Assay

Compounds active in the HBV assembly assay are tested for their activityand toxicity in cellular assay. In the first anti-viral assay, theability of compounds to inhibit HBV replication in an HBV-producinghepatoma cell line using the dot-blot method is evaluated.

Briefly, confluent monolayers of HepG2-2.2.15 cells are incubated withcomplete medium containing various concentrations of a test compound.Three days later, the culture medium is replaced with fresh mediumcontaining the appropriately diluted test compound. Six days followingthe initial administration of the test compound, the cell culturesupernatant is collected, and cell lysis is performed. The samples areapplied onto Nylos membranes and DNA is immobilized to the membrane byUV cross-linking. After pre-hybridization, the HBV probe is added andthe hybridization is performed overnight. The membranes are exposed tothe Kodak films; antiviral activity is calculated from the reduction inHBV DNA levels (EC₅₀). The EC₅₀ for antiviral activity is calculatedfrom the dose response curves of active compounds. Assay performanceover time is monitored by the use of the standard positive controlcompounds ETV, BAY 41-4109, and HAP-1.

Compound cytotoxity (TC₅₀) is measured in this same HepG2-2.2.15 cellline using a CellTiter Blue-based cytotoxicity assay employed asrecommended by manufacturer (Promega). To confirm and expand theseresults, a second antiviral assay is carried out on active compoundsusing the stable HBV cell line HepG2.2.15 and measuring anti-HBV potencyby real-time PCR and cytotoxicity by CellTiter Blue. In this assay, 24hours after cell seeding, HepG2-2.2.15 cells are incubated with completemedium containing various concentrations of a test compound with BAY41-4109 and HAP-1 used as positive controls. After three days, theculture medium is replaced with fresh medium containing theappropriately diluted test compound. The cell culture is collected sixdays following the initial administration of the test compound, followedby HBV DNA extraction using QIAamp 96 DNA Blood Kit (Qiagen). Theextracted HBV DNA is diluted and analyzed by Real-Time PCR. A standardcurve is generated by plotting Ct value vs the amount of HBV plasmidstandard. Cytotoxicity is determined similarly to the above describedmethod by applying a dye uptake method (CellTiter Blue kit, Promega).

Selected compounds were tested for their activity and toxicity incellular assay. In the first anti-viral assay, the ability of compoundsto inhibit HBV replication in an HBV-producing hepatoma cell line usingthe dot-blot method was evaluated.

Confluent monolayers of HepG2-2.2.15 cells were incubated with completemedium containing various concentrations of a test compound. Three dayslater, the culture medium was replaced with fresh medium containing theappropriately diluted test compound. Six days following the initialadministration of the test compound, the cell culture supernatant wascollected, and cell lysis was performed. The samples were applied ontoNylos membranes and DNA was immobilized to the membrane by UVcross-linking. After pre-hybridization, the HBV probe was added and thehybridization was performed overnight. The membranes were exposed to theKodak films; antiviral activity was calculated from the reduction in HBVDNA levels (EC₅₀). The EC₅₀ for antiviral activity was calculated fromthe dose response curves of active compounds. Assay performance overtime was monitored by the use of the standard positive control compoundsETV, BAY 41-4109, and HAP-1. Results for selected compounds of theinvention are illustrated in Table 5.

Cytotoxity (CC₅₀) was measured in this same HepG2-2.2.15 cell line usinga CellTiter Blue-based cytotoxicity assay employed as recommended bymanufacturer (Promega).

TABLE 5 “Activity” represents activity in dot-blot-assay (‘+’indicates >50% activity at 10 μM) Compound Activity 1763_E1 + 1763_E2 +1765 + 1766_E1 + 1766_E2 + 1768 + 1769 + 1819 + 1820 + 1821 + 1821_D1 +1821_D2 + 1822_D1 + 1822_D2 + 1826_D2 + 1829_D1 + 1829_D2 + 1829-2 +1890 + 1891 + 1892 + 1893 + 1893_E1 + 1893_E2 + 1894 + 1895 + 1909 +1910 + 1914 + 1915 + 1916 + 1917 + 1919 + 1938 + 1944 + 1975 + 1977 +1979 + 1980 + 1981 + 1983 + 1986 + 1987 + 1989 + 2002 + 2004 + 2007 +2024 + 2033 + 2114_D1 + 2114_D2 + 2121 + 2123 + 2199 + 2202 + 2205 +2206 + 2433_D1 + 2433_D2 + 2492 + 2505 + 2547 + 2548 + 2550 + 2617_D2 +2618_D1 + 2618_D2 + 2619_D2 + 2625_D2 + 2626_D2 +

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

The invention claimed is:
 1. A compound of Formula Va:

or a pharmaceutically acceptable salt thereof; wherein each R¹ is,independently at each occurrence, halo, OH, —C₁-C₆ alkyl, or —O—C₁-C₆alkyl, wherein the alkyl groups are optionally substituted 1-3 timeswith halo or OH; each R² is, independently at each occurrence, halo, OH,—C₁-C₆ alkyl, or —O—C₁-C₆ alkyl, wherein the alkyl groups are optionallysubstituted 1-3 times with halo or OH; x is 2 or 3; Cy is

and R¹¹ is, independently at each occurrence, —OH, halo, —C₁-C₆ alkyl,—OC(O)CH₃, or —H₂PO₄, wherein n and m are 1, 2, or 3, and at least oneR¹¹ is


2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹ is, independently at each occurrence, halo. 3.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R² is, independently at each occurrence, halo or —C₁-C₆alkyl, wherein the alkyl is optionally substituted 1-3 times with halo.4. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from:


5. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound is